IL24

Gene Summary

Gene:IL24; interleukin 24
Aliases: C49A, FISP, MDA7, MOB5, ST16, IL10B
Location:1q32
Summary:This gene encodes a member of the IL10 family of cytokines. It was identified as a gene induced during terminal differentiation in melanoma cells. The protein encoded by this gene can induce apoptosis selectively in various cancer cells. Overexpression of this gene leads to elevated expression of several GADD family genes, which correlates with the induction of apoptosis. The phosphorylation of mitogen-activated protein kinase 14 (MAPK7/P38), and heat shock 27kDa protein 1 (HSPB2/HSP27) are found to be induced by this gene in melanoma cells, but not in normal immortal melanocytes. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:interleukin-24
HPRD
Source:NCBIAccessed: 17 August, 2015

Ontology:

What does this gene/protein do?
IL24 is implicated in:
- apoptotic process
- cytokine activity
- extracellular space
Data from Gene Ontology via CGAP
Pathways:What pathways are this gene/protein implicaed in?
Show (2)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 17 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 17 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: IL24 (cancer-related)

Sarkar S, Quinn BA, Shen X, et al.
Reversing translational suppression and induction of toxicity in pancreatic cancer cells using a chemoprevention gene therapy approach.
Mol Pharmacol. 2015; 87(2):286-95 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Pancreatic cancer is an aggressive disease with limited therapeutic options. Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24), a potent antitumor cytokine, shows cancer-specific toxicity in a vast array of human cancers, inducing endoplasmic reticulum stress and apoptosis, toxic autophagy, an antitumor immune response, an antiangiogenic effect, and a significant "bystander" anticancer effect that leads to enhanced production of this cytokine through autocrine and paracrine loops. Unfortunately, mda-7/IL-24 application in pancreatic cancer has been restricted because of a "translational block" occurring after Ad.5-mda-7 gene delivery. Our previous research focused on developing approaches to overcome this block and increase the translation of the MDA-7/IL-24 protein, thereby promoting its subsequent toxic effects in pancreatic cancer cells. We demonstrated that inducing reactive oxygen species (ROS) after adenoviral infection of mda-7/IL-24 leads to greater translation into MDA-7/IL-24 protein and results in toxicity in pancreatic cancer cells. In this study we demonstrate that a novel chimeric serotype adenovirus, Ad.5/3-mda-7, displays greater efficacy in delivering mda-7/IL-24 compared with Ad.5-mda-7, although overall translation of the protein still remains low. We additionally show that d-limonene, a dietary monoterpene known to induce ROS, is capable of overcoming the translational block when used in combination with adenoviral gene delivery. This novel combination results in increased polysome association of mda-7/IL-24 mRNA, activation of the preinitiation complex of the translational machinery in pancreatic cancer cells, and culminates in mda-7/IL-24-mediated toxicity.

Wei X, Liu L, Wang G, et al.
Potent antitumor activity of the Ad5/11 chimeric oncolytic adenovirus combined with interleukin-24 for acute myeloid leukemia via induction of apoptosis.
Oncol Rep. 2015; 33(1):111-8 [PubMed] Related Publications
The Ad5/11 chimeric oncolytic adenovirus represents a promising new platform for anticancer therapy. Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of hematopoietic progenitor cells and is the most common malignant myeloid disorder in adults. Myeloid and other hematopoietic cell lineages are involved in the process of clonal proliferation and differentiation. In the present study, we aimed to ascertain whether chimeric oncolytic adenovirus-mediated transfer of the human interleukin-24 (IL-24) gene induces enhanced antitumor potency. Our results showed that the Ad5/11 chimeric oncolytic adenovirus carrying hIL-24 (AdCN205‑11-IL-24) produced high levels of hIL-24 in AML cancer cells, as compared with the Ad5 oncolytic adenovirus expressing hIL-24 (AdCN205-IL-24). AdCN205-11-IL-24 specifically induced a cytotoxic effect on AML cancer cells, but had little or no effect on a normal cell line. AdCN205-11-IL-24 induced higher antitumor activity in AML cancer cells by inducing apoptosis in vitro. This study suggests that transfer of IL-24 by an Ad5/11 chimeric oncolytic adenovirus may be a potent antitumor approach for AML cancer therapy.

Tian H, Zhang D, Gao Z, et al.
MDA-7/IL-24 inhibits Nrf2-mediated antioxidant response through activation of p38 pathway and inhibition of ERK pathway involved in cancer cell apoptosis.
Cancer Gene Ther. 2014; 21(10):416-26 [PubMed] Related Publications
Reactive oxygen species (ROS) have a crucial role in melanoma differentiation-associated gene-7 (MDA-7)/interleukin-24 (IL-24)-induced cancer cell apoptosis. However, cancer cell has a series of protective mechanisms to resist ROS damage. Nuclear factor erythroid 2-related factor 2 (Nrf2) activates antioxidant response element (ARE)-mediated gene expression involved in cellular protection against oxidative stress. As the Nrf2 repressor, Kelch-like ECH-associated protein-1 (Keap1) sequesters Nrf2 in cytoplasm to block Nrf2 nuclear translocation. In the present study, administration of MDA-7/IL-24 by means of tumor-selective replicating adenovirus (ZD55-IL-24) was used to investigate whether ZD55-IL-24 could attenuate Nrf2-mediated oxidative stress response in cancer cell. We found that ZD55-IL-24 effectively strengthened the association between Nrf2 and Keap1 to restrict Nrf2 nuclear translocation, thereby inhibiting ARE-dependent transcriptional response. To evaluate the detailed mechanism underlying the suppression of ZD55-IL-24 on Nrf2-mediated oxidative stress response, we further tested three different mitogen-activated protein kinase (MAPK) signaling pathways in A549 and HeLa cells transfected by ZD55-IL-24. Our data showed that ZD55-IL-24 inhibited extracellular signal-regulated kinase (ERK) signal pathway but activated p38 and c-Jun-NH2-kinase (JNK) signal pathways to exert the tumor-specific apoptosis. Moreover, ERK pathway inhibitor U0126 prevented Nrf2 phosphorylation at Ser40 to retard Nrf2 nuclear translocation, thus decreasing antioxidant gene transcription. In contrast, p38 pathway inhibitor SB203580 obviously promoted the dissociation of Nrf2 from Keap1 to promote antioxidant gene transcription. However, JNK pathway had no effect on Nrf2 subcellular localization or the association of Nrf2 with Keap1. Conclusively, our results indicate that ZD55-IL-24 inhibits Nrf2-mediated oxidative stress response not only by activating p38 signal pathway to potentiate the association of Nrf2 and Keap1 but also by suppressing ERK signal pathway to postpone Nrf2 nuclear translocation. Given the 'dark' side of Nrf2 on carcinoma cell survival and chemoresistance, our study provides a novel explanation about MDA-7/IL-24-induced cancer-specific apoptosis and therapeutic sensitization through suppression of the cytoprotective system.

Wang L, Feng Z, Wu H, et al.
Melanoma differentiation-associated gene-7/interleukin-24 as a potential prognostic biomarker and second primary malignancy indicator in head and neck squamous cell carcinoma patients.
Tumour Biol. 2014; 35(11):10977-85 [PubMed] Related Publications
The significance of melanoma differentiation-associated gene-7/interleukin-24 (MDA-7/IL-24) expression in head and neck squamous cell carcinoma (HNSCC) remains unclear. This study was designed to investigate and evaluate the clinical significance of MDA-7/IL-24 expression in HNSCC by detecting expression by immunostaining in 131 HNSCC specimens. The function of MDA-7/IL-24 was investigated by real-time polymerase chain reaction (PCR) and Western blot in Ad5.mda-7-infected HNSCC cell lines. Our results showed that MDA-7/IL-24 was mainly expressed in the cytoplasm of HNSCC cells. MDA-7/IL-24 high patients presented with a favorable postoperative prognosis compared with MDA-7/IL-24 low patients, and high expression of MDA-7/IL-24 was significantly correlated with a lower incidence of second primary malignancies (SPMs) in the head and neck regions. In vitro assays showed that high expression of MDA-7/IL-24 could upregulate the expression of the epithelial terminal differentiation markers cytokeratin (KRT) 1, KRT4, KRT13, phosphorylated endoplasmic reticulum stress protein (p)-EIF2a, and the apoptosis-related protein cleaved caspase-3. It also downregulated the epithelial proliferative markers KRT5, KRT14, Integrin β4, and anti-apoptosis protein Bcl-2, which might be partially involved in the underlying mechanisms of Ad.mda-7-mediated HNSCC differentiation and apoptosis. Our results indicate that MDA-7/IL-24 can be a prognostic biomarker and an indicator of second primary malignancies (SPM) in HNSCC.

Menezes ME, Bhatia S, Bhoopathi P, et al.
MDA-7/IL-24: multifunctional cancer killing cytokine.
Adv Exp Med Biol. 2014; 818:127-53 [PubMed] Related Publications
First identified almost two decades ago as a novel gene differentially expressed in human melanoma cells induced to terminally differentiate, MDA-7/IL-24 has since shown great potential as an anti-cancer gene. MDA-7/IL24, a secreted protein of the IL-10 family, functions as a cytokine at normal physiological levels and is expressed in tissues of the immune system. At supra-physiological levels, MDA-7/IL-24 plays a prominent role in inhibiting tumor growth, invasion, metastasis and angiogenesis and was recently shown to target tumor stem/initiating cells for death. Much of the attention focused on MDA-7/IL-24 originated from the fact that it can selectively induce cell death in cancer cells without affecting normal cells. Thus, this gene originally shown to be associated with melanoma cell differentiation has now proven to be a multi-functional protein affecting a broad array of cancers. Moreover, MDA-7/IL-24 has proven efficacious in a Phase I/II clinical trial in humans with multiple advanced cancers. As research in the field progresses, we will unravel more of the functions of MDA-7/IL-24 and define novel ways to utilize MDA-7/IL-24 in the treatment of cancer.

Pal I, Sarkar S, Rajput S, et al.
BI-69A11 enhances susceptibility of colon cancer cells to mda-7/IL-24-induced growth inhibition by targeting Akt.
Br J Cancer. 2014; 111(1):101-11 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
BACKGROUND: Akt and its downstream signalling pathways contribute to the aetiology and progression of colorectal carcinoma (CRC). Targeting the Akt pathway is an attractive strategy but few chemotherapeutic drugs have been used to treat CRC with only limited success. BI-69A11, a small molecule inhibitor of Akt, efficiently inhibits growth in melanoma cells. Melanoma differentiation associated gene-7 (mda-7)/interleukin-24 promotes cancer-selective apoptosis when delivered by a tropism-modified replication incompetent adenovirus (Ad.5/3-mda-7). However, Ad.5/3-mda-7 displays diminished antitumour efficacy in several CRC cell lines, which correlates with the expression of K-RAS.
METHODS: The individual and combinatorial effect of BI-69A11 and Ad.5/3-mda-7 in vitro was studied by cell viability, cell cycle, apoptosis and invasion assays in HT29 and HCT116 cells containing wild type or mutant K-ras, respectively. In vivo HT29 tumour xenografts were used to test the efficacy of the combination treatment.
RESULTS: BI-69A11 inhibited growth and induced apoptosis in CRC. However, combinatorial treatment was more effective compared with single treatment. This combination showed profound antitumour and anti angiogenic effects in vitro and in vivo by downregulating Akt activity.
CONCLUSIONS: BI-69A11 enhances the antitumour efficacy of Ad.5/3-mda-7 on CRC overexpressing K-RAS by inducing apoptosis and regulating Akt activity thereby warranting further evaluation in treating CRC.

Jiang G, Yang CS, Xu D, et al.
Potent anti-tumour activity of a novel conditionally replicating adenovirus for melanoma via inhibition of migration and invasion.
Br J Cancer. 2014; 110(10):2496-505 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
BACKGROUND: Conditionally replicating adenoviruses (CRAds) represent a novel class of oncological therapeutic agents. One strategy to ensure tumour targeting is to place the essential viral genes under the control of tumour-specific promoters. Ki67 has been selected as a cancer gene therapy target, as it is expressed in most malignant cells but is barely detectable in most normal cells. This study aimed to investigate the effects of a Ki67 promoter-controlled CRAd (Ki67-ZD55-IL-24) on the proliferation and apoptosis of melanoma cells.
METHODS: Melanoma cells were independently treated with Ki67-ZD55-IL-24, ZD55-IL-24, Ki67-ZD55, and ZD55-EGFP. The cytotoxic potential of each treatment was assessed using cell viability measurements. Cell migration and invasion were assayed using cell migration and invasion assays. Apoptosis was assayed using the annexin V-FITC assay, western blotting, reverse transcriptase PCR (RT-PCR), haematoxylin and eosin (H&E) staining, and the TUNEL assay.
RESULTS: Our results showed that Ki67-ZD55-IL-24 had significantly enhanced anti-tumour activity as it more effectively induced apoptosis in melanoma cells than the other agents. Ki67-ZD55-IL-24 also caused the most significant inhibition of cell migration and invasion of melanoma cells. Furthermore, apoptosis was induced more effectively in melanoma xenografts in nude mice.
CONCLUSIONS: This strategy holds promising potential for the further development of an effective approach to treat malignant melanoma.

Ma G, Kawamura K, Shan Y, et al.
Combination of adenoviruses expressing melanoma differentiation-associated gene-7 and chemotherapeutic agents produces enhanced cytotoxicity on esophageal carcinoma.
Cancer Gene Ther. 2014; 21(1):31-7 [PubMed] Related Publications
We examined the combinatory antitumor effects of adenoviruses expressing human mda-7/IL-24 gene (Ad-mda-7) and chemotherapeutic agents on nine kinds of human esophageal carcinoma cells. All the carcinoma cells expressed the melanoma differentiation-associated gene-7/interleukin-24 (MDA-7/IL-24) receptor complexes, IL-20R2 and either IL-20R1 or IL-22R1, and were susceptible to Ad-mda-7, whereas fibroblasts were positive only for IL-20R2 gene and resistant to Ad-mda-7-mediated cytotoxicity. Sensitivity of these esophageal carcinoma cells to Ad-mda-7 was however lower than that to Ad expressing the wild-type p53 gene. We thereby investigated a possible combination of Ad-mda-7 and anticancer agents and found that Ad-mda-7 with 5-fluorouracil (5-FU), cisplatin, mitomycin C or etoposide produced greater cytotoxic effects than those by Ad-mda-7 or the agent alone. Half-maximal inhibitory concentration values of the agents in respective cells were decreased by the combination with Ad-mda-7. Cell cycle analyses showed that Ad-mda-7 and 5-FU increased G2/M-phase and S-phase populations, respectively, and the combination augmented sub-G1 populations. Ad-mda-7-treated cells showed cleavages of caspase-8, -9 and -3 and poly (ADP-ribose) polymerase, but the cleavage levels were not different from those of the combination-treated cells. Ad-mda-7 treatments upregulated Akt phosphorylation but suppressed IκB-α levels, whereas 5-FU treatments induced phosphorylation of p53 and extracellular signal-regulated protein kinases 1 and 2. Molecular changes caused by the combination were similar to those by Ad-mda-7 treatments, but the Ad-mda-7-mediated upregulation of Akt phosphorylation decreased with the combination. These data collectively suggest that Ad-mda-7 induced apoptosis despite Akt activation and that the combinatory antitumor effects with 5-FU were produced partly by downregulating the Ad-mda-7-induced Akt activation.

Xu Y, Zhang F, Qin L, et al.
Enhanced in-vitro and in-vivo suppression of A375 melanoma by combined IL-24/OSM adenoviral-mediated gene therapy.
Melanoma Res. 2014; 24(1):20-31 [PubMed] Related Publications
Interleukin-24 (IL-24)/melanoma differentiation-associated gene-7 (mda-7) is a unique cytokine-tumor suppressor that displays ubiquitous antitumor properties and tumor-specific killing activity. Oncostatin M (OSM) is the most active IL-6-type cytokine and inhibits the proliferation of various solid tumor cell lines. Multigene-based combination therapy may be an effective practice in cancer gene therapy. The therapeutic potential of a combination of IL-24 and OSM in treating cancers is still elusive. In this study, we aimed to examine the enhanced antitumor activity of adenovirus-mediated IL-24/OSM tumor suppressor gene cotransfer in human melanoma cells. We constructed an IL-24/OSM bicistronic adenovirus and assessed its combined effect on A375 human melanoma cells in vitro and in vivo by detecting and comparing apoptosis in the bicistronic antioncogene group (Ad-IL-24-OSM) and in the IL-24 or OSM single antioncogene group. We also investigated the possible mechanism underlying this effect. The bicistronic adenovirus-mediated coexpression of IL-24 and OSM induced additive growth suppression and apoptosis and an overlapping effect on the upregulation of p21, p53, Bax, and cleaved caspase-3 in vitro and in vivo. Moreover, Ad-IL-24-OSM treatment additively reduced the expression of CDK4 and cyclin D1 in A375 melanoma cells and the expression of CD34 and Cox-2 in A375 xenograft tumors in athymic nude mice. The enhanced antitumor activity elicited by Ad-IL-24-OSM was closely associated with the activation of the apoptotic pathway and the additive inhibition of tumor angiogenesis. Therefore, our results indicate that cancer gene therapy combining two or more tumor suppressors, such as IL-24 and OSM, may constitute a novel and effective therapeutic strategy for treating malignant melanoma and other cancers.

Dash R, Bhoopathi P, Das SK, et al.
Novel mechanism of MDA-7/IL-24 cancer-specific apoptosis through SARI induction.
Cancer Res. 2014; 74(2):563-74 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Subtraction hybridization combined with induction of cancer cell terminal differentiation in human melanoma cells identified melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) and SARI (suppressor of AP-1, induced by IFN) that display potent antitumor activity. These genes are not constitutively expressed in cancer cells and forced expression of mda-7/IL-24 (Ad.mda-7) or SARI (Ad.SARI) promotes cancer-specific cell death. Ectopic expression of mda-7/IL-24 induces SARI mRNA and protein in a panel of different cancer cells, leading to cell death, without harming corresponding normal cells. Simultaneous inhibition of K-ras downstream extracellular signal-regulated kinase 1/2 signaling in pancreatic cancer cells reverses the translational block of MDA-7/IL-24 and induces SARI expression and cell death. Using SARI-antisense-based approaches, we demonstrate that SARI expression is necessary for mda-7/IL-24 antitumor effects. Secreted MDA-7/IL-24 protein induces antitumor "bystander" effects by promoting its own expression. Recombinant MDA-7/IL-24 (His-MDA-7) induces SARI expression, supporting the involvement of SARI in the MDA-7/IL-24-driven autocrine loop, culminating in antitumor effects. Moreover, His-MDA-7, after binding to its cognate receptors (IL-20R1/IL-20R2 or IL-22R/IL-20R2), induces intracellular signaling by phosphorylation of p38 MAPK, leading to transcription of a family of growth arrest and DNA damage inducible (GADD) genes, culminating in apoptosis. Inhibition of p38 MAPK fails to induce SARI following Ad.mda-7 infection. These findings reveal the significance of the mda-7/IL-24-SARI axis in cancer-specific killing and provide a potential strategy for treating both local and metastatic disease.

Mitsui H, Suárez-Fariñas M, Gulati N, et al.
Gene expression profiling of the leading edge of cutaneous squamous cell carcinoma: IL-24-driven MMP-7.
J Invest Dermatol. 2014; 134(5):1418-27 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
The precise mechanisms governing invasion at the leading edge of squamous cell carcinoma (SCC) and its subsequent metastasis are not fully understood. We aimed to define the cancer-related molecular changes that distinguish noninvasive tumor from invasive SCC. To this end, we combined laser capture microdissection with complementary DNA (cDNA) microarray analysis. We defined invasion-associated genes as those differentially regulated only in invasive SCC nests, but not in actinic keratosis or in situ SCC, compared with normal epidermis. There were 383 upregulated and 354 downregulated genes in the "invasion set." SCC invasion was characterized by aberrant expression of various proteolytic molecules. We noted increased expression of MMP7 and IL-24 in invasive SCC. IL-24 induced the expression of matrix metallopeptidase 7 (MMP7) in SCC cells in culture. In addition, blocking of MMP7 by a specific antibody significantly delayed the migration of SCC cells in culture. These results suggest a possible contribution of IL-24 to SCC invasion via enhancing focal expression of MMP7, although IL-24 has been suggested to have antitumor growth effects in other cancer types. Identification of regional molecular changes that regulate cancer invasion may facilitate the development of new targeted treatments for aggressive cancer.

Zhang Z, Kawamura K, Jiang Y, et al.
Heat-shock protein 90 inhibitors synergistically enhance melanoma differentiation-associated gene-7-mediated cell killing of human pancreatic carcinoma.
Cancer Gene Ther. 2013; 20(12):663-70 [PubMed] Related Publications
Pancreatic cancer is one of the intractable diseases and an effective therapeutic strategy is required to improve the prognosis. We examined possible antitumor effects of adenoviruses expressing melanoma differentiation-associated gene-7/interleukin-24 (Ad-mda-7) and a heat-shock protein 90 (Hsp90) inhibitor to human pancreatic carcinoma cells. Ad-mda-7 and an Hsp90 inhibitor, geldanamycin (GA), produced cytotoxic effects, and a combinatory use of Ad-mda-7 and GA further achieved synergistic effects. Administration of N-acetyl-L-cysteine, an inhibitor of reactive oxygen species, eliminated Ad-mda-7- and GA-mediated cytotoxicity. Ad-mda-7 augmented phosphorylated AKT levels but GA did not influence the phosphorylation. GA-treated cells showed cleavage of poly-(ADP-ribose) polymerase but not caspase-3, and upregulated Hsp70 and LC3A/B II levels, whereas Ad-mda-7-treated cells did not. GA treatments augmented ubiquitination and markedly increased melanoma differentiation-associated gene-7 (MDA-7) expression levels. These findings suggest that Ad-mda-7-mediated cytotoxicity is dependent on reactive oxygen species but independent of apoptosis or autophagy, and that GA-mediated cytotoxicity was linked with caspase-independent apoptosis and/or autophagy. A mechanism underlying the combinatory effects of Ad-mda-7 and GA remained complex and the synergism is attributable to multiple factors including increased MDA-7 protein stability by GA.

Heckmann D, Maier P, Laufs S, et al.
The disparate twins: a comparative study of CXCR4 and CXCR7 in SDF-1α-induced gene expression, invasion and chemosensitivity of colon cancer.
Clin Cancer Res. 2014; 20(3):604-16 [PubMed] Related Publications
PURPOSE: In colorectal cancer, increased expression of the CXC chemokine receptor 4 (CXCR4) has been shown to provoke metastatic disease due to the interaction with its ligand stromal cell-derived factor-1 (SDF-1). Recently, a second SDF-1 receptor, CXCR7, was found to enhance tumor growth in solid tumors. Albeit signaling cascades via SDF-1/CXCR4 have been intensively studied, the significance of the SDF-1/CXCR7-induced intracellular communication triggering malignancy is still only marginally understood.
EXPERIMENTAL DESIGN: In tumor tissue of 52 patients with colorectal cancer, we observed that expression of CXCR7 and CXCR4 increased with tumor stage and tumor size. Asking whether activation of CXCR4 or CXCR7 might result in a similar expression pattern, we performed microarray expression analyses using lentivirally CXCR4- and/or CXCR7-overexpressing SW480 colon cancer cell lines with and without stimulation by SDF-1α.
RESULTS: Gene regulation via SDF-1α/CXCR4 and SDF-1α/CXCR7 was completely different and partly antidromic. Differentially regulated genes were assigned by gene ontology to migration, proliferation, and lipid metabolic processes. Expressions of AKR1C3, AXL, C5, IGFBP7, IL24, RRAS, and TNNC1 were confirmed by quantitative real-time PCR. Using the in silico gene set enrichment analysis, we showed that expressions of miR-217 and miR-218 were increased in CXCR4 and reduced in CXCR7 cells after stimulation with SDF-1α. Functionally, exposure to SDF-1α increased invasiveness of CXCR4 and CXCR7 cells, AXL knockdown hampered invasion. Compared with controls, CXCR4 cells showed increased sensitivity against 5-FU, whereas CXCR7 cells were more chemoresistant.
CONCLUSIONS: These opposing results for CXCR4- or CXCR7-overexpressing colon carcinoma cells demand an unexpected attention in the clinical application of chemokine receptor antagonists such as plerixafor.

Sarkar S, Azab B, Quinn BA, et al.
Chemoprevention gene therapy (CGT) of pancreatic cancer using perillyl alcohol and a novel chimeric serotype cancer terminator virus.
Curr Mol Med. 2014; 14(1):125-40 [PubMed] Related Publications
Conditionally replication competent adenoviruses (Ads) that selectively replicate in cancer cells and simultaneously express a therapeutic cytokine, such as melanoma differentiation associated gene- 7/Interleukin-24 (mda-7/IL-24), a Cancer Terminator Virus (CTV-M7), hold potential for treating human cancers. To enhance the efficacy of the CTV-M7, we generated a chimeric Ad.5 and Ad.3 modified fiber bipartite CTV (Ad.5/3-CTV-M7) that can infect tumor cells in a Coxsackie Adenovirus receptor (CAR) independent manner, while retaining high infectivity in cancer cells containing high CAR. Although mda-7/IL-24 displays broad-spectrum anticancer properties, pancreatic ductal adenocarcinoma (PDAC) cells display an intrinsic resistance to mda-7/IL-24-mediated killing due to an mda-7/IL-24 mRNA translational block. However, using a chemoprevention gene therapy (CGT) approach with perillyl alcohol (POH) and a replication incompetent Ad to deliver mda-7/IL-24 (Ad.mda-7) there is enhanced conversion of mda-7/IL-24 mRNA into protein resulting in pancreatic cancer cell death in vitro and in vivo in nude mice containing human PDAC xenografts. This combination synergistically induces mda-7/IL-24-mediated cancer-specific apoptosis by inhibiting anti-apoptotic Bcl-xL and Bcl-2 protein expression and inducing an endoplasmic reticulum (ER) stress response through induction of BiP/GRP-78, which is most evident in chimeric-modified non-replicating Ad.5/3- mda-7- and CTV-M7-infected PDAC cells. Moreover, Ad.5/3-CTV-M7 in combination with POH sensitizes therapy-resistant MIA PaCa-2 cell lines over-expressing either Bcl-2 or Bcl-xL to mda-7/IL-24-mediated apoptosis. Ad.5/3-CTV-M7 plus POH also exerts a significant antitumor 'bystander' effect in vivo suppressing both primary and distant site tumor growth, confirming therapeutic utility of Ad.5/3-CTV-M7 plus POH in PDAC treatment, where all other current treatment strategies in clinical settings show minimal efficacy.

Zhuo B, Wang R, Zhang H, et al.
Interleukin-24 inhibits cell migration and invasion in the neuroblastoma cell line SH-SY5Y.
Oncol Rep. 2013; 30(6):2749-54 [PubMed] Related Publications
Neuroblastomas are common pediatric solid tumors with a variable clinical course; approximately 50% of patients present with metastatic disease at diagnosis. The development of metastatic lesions often causes a fatal outcome. Therefore, the prevention of metastases during the early stage of tumor development is critical for the improvement of the prognosis of neuroblastoma patients. We previously observed the suppression of neuroblastoma growth in response to overexpression of interleukin-24 (IL-24) in vitro and in vivo. IL-24 exerts its tumor-suppressive effects by multiple mechanisms, including the balance of Bcl-2 family proteins toward the pro-apoptotic pathway and the activation of the caspase cascade. In this study, we used adenovirus-mediated IL-24 (Ad-IL24) to examine the effect of the ectopic production of IL-24 on cell migration and invasion in human neuroblastoma cells. We found that IL-24 effectively inhibits SH-SY5Y neuroblastoma cell migration and invasion by changing subcellular localization and cellular levels of β-catenin and regulating the levels of proteins associated with cell migration and invasion. Thus, IL-24 should be considered a therapeutic agent that can inhibit primary neuroblastoma growth and that may prevent metastasis.

Hamed HA, Das SK, Sokhi UK, et al.
Combining histone deacetylase inhibitors with MDA-7/IL-24 enhances killing of renal carcinoma cells.
Cancer Biol Ther. 2013; 14(11):1039-49 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
In the present study we show that histone deacetylase inhibitors (HDACIs) enhance the anti-tumor effects of melanoma differentiation associated gene-7/interleukin 24 (mda- 7/IL-24) in human renal carcinoma cells. Similar data were obtained in other GU tumor cells. Combination of these two agents resulted in increased autophagy that was dependent on expression of ceramide synthase 6, with HDACIs enhancing MDA-7/IL-24 toxicity by increasing generation of ROS and Ca (2+). Knock down of CD95 protected cells from HDACI and MDA-7/IL-24 lethality. Sorafenib treatment further enhanced (HDACI + MDA-7/IL-24) lethality. Anoikis resistant renal carcinoma cells were more sensitive to MDA-7/IL-24 that correlated with elevated SRC activity and tyrosine phosphorylation of CD95. We employed a recently constructed serotype 5/3 adenovirus, which is more effective than a serotype 5 virus in delivering mda- 7/IL-24 to renal carcinoma cells and which conditionally replicates (CR) in tumor cells expressing MDA-7/IL-24 by virtue of placing the adenoviral E1A gene under the control of the cancer-specific promoter progression elevated gene-3 (Ad.5/3-PEG-E1A-mda-7; CRAd.5/3-mda-7, Ad.5/3-CTV), to define efficacy in renal carcinoma cells. Ad.5/3-CTV decreased the growth of renal carcinoma tumors to a significantly greater extent than did a non-replicative virus Ad.5/3-mda-7. In contralateral uninfected renal carcinoma tumors Ad.5/3-CTV also decreased the growth of tumors to a greater extent than did Ad.5/3-mda-7. In summation, our data demonstrates that HDACIs enhance MDA-7/IL-24-mediated toxicity and tumor specific adenoviral delivery and viral replication of mda-7/IL-24 is an effective pre-clinical renal carcinoma therapeutic.

Mao Z, Bian G, Sheng W, et al.
Adenovirus-mediated IL-24 expression enhances the chemosensitivity of multidrug-resistantgastric cancer cells to cisplatin.
Oncol Rep. 2013; 30(5):2288-96 [PubMed] Related Publications
Chemotherapy is one of the commonly used strategies in gastric cancer, especially for unresectable patients, but it becomes insensitive to repeated administration of even the most effective chemotherapeutic agents, such as cisplatin. Given this, there is an urgent need for developing chemosensitizers to overcome acquired resistance to chemotherapeutic agents. Interleukin-24 (IL-24), a cytokine-tumor suppressor, shows broad-spectrum and tumor-specific antitumor properties, and studies have demonstrated that IL-24 could conspicuously restore the chemosensitivity of MDR cancer cells. Herein, we developed a human MDR gastric cancer cell subline, SGC7901/CDDP, by repeated selection of resistant clones of parental sensitive cells, and further investigated the chemosensitizing effects and the underlying mechanisms of adenovirus-mediated IL-24 (Ad-IL-24) gene therapy plus CDDP for the human MDR gastric cancer cells SGC7901/CDDP in vitro and in vivo. The results demonstrated that the expression of IL-24 mRNA and protein was profoundly downregulated in SGC7901/CDDP cells by RT-PCR and western blot analysis. In addition, the cell viability assay showed that the IC50 of SGC7901/CDDP cells to CDDP, 5-FU, ADM and MTX was significantly enhanced compared to parental sensitive SGC7901 cells. Ad-IL-24-induced IL-24 overexpression decreased the IC50 of the above agents (not MTX), induced G2/M cell cycle arrest, and Ad-IL-24 plus CDDP elicited significant apoptosis and tumor suppression of SGC7901/CDDP cells in vitro and SGC7901/CDDP cell xenograft tumors in vivo, respectively. Moreover, our results demonstrated that the mechanisms of Ad-IL-24-elicited chemosensitizing effects were closely associated with a substantial upregulation of Bax and downregulation of P-gp and Bcl-2 in SGC7901/CDDP cells in vitro and SGC7901/CDDP xenograft tissues in vivo. Thus, this study indicates that overexpression of IL-24 gene can significantly promote chemosensitivity in MDR phenotype SGC7901/CDDP gastric cancer cells.

Yuan L, Zhao H, Zhang L, Liu X
The efficacy of combination therapy using adeno-associated virus-mediated co-expression of apoptin and interleukin-24 on hepatocellular carcinoma.
Tumour Biol. 2013; 34(5):3027-34 [PubMed] Related Publications
Multigene-based combination therapy is an effective practice in cancer gene therapy. Apoptin is a chicken anemia virus-derived, p53-independent, Bcl-2-insensitive apoptotic protein with the ability to specifically induce apoptosis in various human tumor cells. Interleukin-24 (IL-24) displays ubiquitous antitumor property and tumor-specific killing activity. Adeno-associated virus (AAV) is a promising gene delivery vehicle due to its advantage of low pathogenicity and long-term gene expression. In this study, we assessed the efficacy of combination therapy using AAV-mediated co-expression of apoptin and interleukin-24 on hepatocellular carcinoma in vitro and in vivo. Our results showed that AAV-mediated co-expression of IL-24 and apoptin significantly suppressed the growth and induced the apoptosis of HepG2 cells in vitro. Furthermore, AAV-mediated combined treatment of IL-24 and apoptin significantly suppressed tumor growth and induced apoptosis of tumor cells in xenograft nude mice. These data suggest that AAV vectors that co-express apoptin and IL-24 have great potential in cancer gene therapy.

Wang Q, Zhu Y, Yang P
Is mda-7/IL-24 a potential target and biomarker for enhancing drug sensitivity in human glioma U87 cell line?
Anat Rec (Hoboken). 2013; 296(8):1154-60 [PubMed] Related Publications
Gliomas are the most common form of primary brain tumor with the highest mortality rates. Drug resistance is a major cause of treatment failure in patients with glioma. Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) has been demonstrated to play an important role in drug resistance in human cancer cell lines. However, the reversing effect of mda-7/IL-24 on drug resistance of human glioma is not fully clear. Here, we investigated the effects of overexpression of the mda-7/IL-24 gene in human glioma. We established a cisplatin-resistant U87 glioma cell line and found that mda-7/IL-24 was highly correlated with drug resistance. Furthermore, we investigated the apoptotic rate, intracellular accumulation of Rhodamine-123, and expression of glutathione and P-glycoprotein. The over-expression of mda-7/IL-24 enhanced cisplatin cytotoxicity and reversal of drug resistance in glioma cells. The reversing effect of mda-7/IL-24 on drug resistance was induced mainly through the regulation of drug resistance-related genes and efflux drug pumps. Thus, mda-7/IL-24 can be used as a promising predictive biomarker and potential therapeutic target for chemotherapy in glioma.

Liu J, Zhang Y, Sun P, et al.
Enhanced therapeutic efficacy of adenovirus-mediated interleukin-24 gene therapy combined with ionizing radiotherapy for nasopharyngeal carcinoma.
Oncol Rep. 2013; 30(3):1165-74 [PubMed] Related Publications
Melanoma differentiation-associated gene-7 (mda-7)/interleukin-24 (IL-24), a unique cytokine tumor suppressor, displays ubiquitous antitumor activities and cancer-specific cytotoxicities via multiple signaling pathways. In the present study, we investigated the antitumor effect of adenovirus-mediated IL-24 (AdVIL-24) gene therapy in conjunction with ionizing radiation on CNE-2Z human nasopharyngeal carcinoma (NPC) cells in vitro and in vivo in athymic nude mice, and its potential mechanisms. We demonstrated that AdVIL-24 gene therapy plus ionizing radiotherapy induced enhanced growth inhibition, cell cycle G1 phase arrest and apoptosis in vitro in CNE-2Z human NPC cells and in vivo in CNE-2Z xenografted tumors subcutaneously implanted in athymic nude mice. Mechanistically, AdVIL-24 combined with ionizing radiation led to the substantial upregulation of P21 and P27 cyclin-dependent kinase (CDK) inhibitors, ratio of pro-apoptotic to anti-apoptotic molecules Bax/Bcl-2 and cleaved caspase‑3 as well as downregulation of cyclin E and CDK2 in vitro and in vivo in CNE-2Z human NPC cells. Furthermore, AdVIL-24 plus radiation additively reduced the tumor vessel CD34 expression and microvessel density in vivo. More importantly, AdVIL-24 potentially blocked the radiation-induced enhancement of vascular endothelial growth factor (VEGF), a pro-angiogenic factor. The enhanced antitumor activity against NPC elicited by AdVIL-24 gene therapy combined with ionizing radiotherapy was closely associated with the enhanced induction of G1 phase arrest and apoptosis via additive modulation of cell cycle regulatory molecules and activation of intrinsic apoptotic pathways, and the overlapping inhibition of tumor angiogenesis. Thus, our results suggest that AdVIL-24 gene therapy combined with ionizing radiotherapy may be a novel and effective treatment strategy for human NPC.

Lin BW, Jiao ZL, Fan JF, et al.
Inhibitory effect of melanoma differentiation associated gene-7/interleukin-24 on invasion in vitro of human melanoma cancer cells.
J Korean Med Sci. 2013; 28(6):833-9 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
The acquisition of metastasis potential is a critical point for malignant tumors. Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) is a potential tumor suppress gene and frequently down-regulated in malignant tumors. It has been implicated that overexpression of MDA-7 led to proliferation inhibition in many types of human tumor. Invasion is an important process which is potential to promote tumor metastasis. However, the role and potential molecular mechanism of mda-7/IL-24 to inhibit the invasion of human melanoma cancer is not fully clear. In this report, we identified a solid role for mda-7/IL-24 in invasion inhibition of human melanoma cancer LiBr cells, including decreasing of adhesion and invasion in vitro, blocking cell cycle, down-regulating the expression of ICAM-1, MMP-2/9, CDK1, the phosphorylation of ERK and Akt, NF-κB and AP-1 transcription activity. Meanwhile, there was an increased expression of PTEN in mda-7/IL-24 over-expression LiBr cells. Our results demonstrated that mda-7/IL-24 is a potential invasion suppress gene, which inhibits the invasion of LiBr cells by the down-regulation of ICAM-1, MMP-2/9, PTEN, and CDK1 expression. The molecular pathways involved were the MAPK/ERK, PI3K-Akt, NF-κB, and AP-1. These findings suggest that mda-7/IL-24 may be used as a possible therapeutic strategy for human melanoma cancer.

Huo W, Li ZM, Zhu XM, et al.
MDA-7/IL-24 suppresses tumor adhesion and invasive potential in hepatocellular carcinoma cell lines.
Oncol Rep. 2013; 30(2):986-92 [PubMed] Related Publications
Melanoma differentiation associated gene-7 (MDA-7)/interleukin‑24 (IL-24) has been considered as a tumor-suppressor gene, which suppresses the growth and induces the apoptosis of cancer cells. In the present study, we investigated the effect and mechanisms of MDA-7/IL-24 regarding the inhibition of metastasis of HepG2 and BEL-7402 human hepatocellular carcinoma (HCC) cells in vitro. We established MDA-7/IL-24-overexpressing HepG2 and BEL-7402 cell lines and found that MDA-7/IL-24 overexpression inhibited tumor cell adhesion and invasion, and induced G2/M arrest in tumor cells. To explore its mechanism of action, western blotting and real-time-PCR assay were used to investigate the expression of E-cadherin, CD44, ICAM-1, matrix metalloproteinase (MMP)-2 and -9, CyclinB, Twist, survivin, p-ERK and p-Akt. ELISA assay was used to measure the secretion of TGF-β, and a reporter gene assay was used to detected the transcriptional activity of NF-κB and AP-1 in HepG2 and BEL-7402 cells. The results showed that MDA-7/IL-24 overexpression decreased the expression of CD44, ICAM-1, MMP-2/-9, CyclinB, Twist, survivin, TGF-β and p-Akt, transcriptional activity of NF-κB, and increased the expression of E-cadherin and p-ERK and transcriptional activity of AP-1 in HepG2 and BEL-7402 cells. Our results revealed that MDA-7/IL-24 mediated the inhibition of adhesion and invasion in HepG2 and BEL-7402 cells by suppressing metastasis-related gene expression. Thus, MDA-7/IL-24 may be used as a novel cancer-suppressor gene for the therapy of human HCC.

Bhutia SK, Das SK, Azab B, et al.
Targeting breast cancer-initiating/stem cells with melanoma differentiation-associated gene-7/interleukin-24.
Int J Cancer. 2013; 133(11):2726-36 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) displays a broad range of antitumor properties including cancer-specific induction of apoptosis, inhibition of tumor angiogenesis and modulation of antitumor immune responses. In our study, we elucidated the role of MDA-7/IL-24 in inhibiting growth of breast cancer-initiating/stem cells. Ad.mda-7 infection decreased proliferation of breast cancer-initiating/stem cells without affecting normal breast stem cells. Ad.mda-7 induced apoptosis and endoplasmic reticulum stress in breast cancer-initiating/stem cells similar to unsorted breast cancer cells and inhibited the self-renewal property of breast cancer-initiating/stem cells by suppressing Wnt/β-catenin signaling. Prevention of inhibition of Wnt signaling by LiCl increased cell survival upon Ad.mda-7 treatment, suggesting that Wnt signaling inhibition might play a key role in MDA-7/IL-24-mediated death of breast cancer-initiating/stem cells. In a nude mouse subcutaneous xenograft model, Ad.mda-7 injection profoundly inhibited growth of tumors generated from breast cancer-initiating/stem cells and also exerted a potent "bystander" activity inhibiting growth of distant uninjected tumors. Further studies revealed that tumor growth inhibition by Ad.mda-7 was associated with a decrease in proliferation and angiogenesis, two intrinsic features of MDA-7/IL-24, and a reduction in vivo in the percentage of breast cancer-initiating/stem cells. Our findings demonstrate that MDA-7/IL-24 is not only nontoxic to normal cells and normal stem cells but also can kill both unsorted cancer cells and enriched populations of cancer-initiating/stem cells, providing further documentation that MDA-7/IL-24 might be a safe and effective way to eradicate cancers and also potentially establish disease-free survival.

Hamed HA, Yacoub A, Park MA, et al.
Histone deacetylase inhibitors interact with melanoma differentiation associated-7/interleukin-24 to kill primary human glioblastoma cells.
Mol Pharmacol. 2013; 84(2):171-81 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
We presently demonstrate that histone deacetylase inhibitors (HDACIs) enhance toxicity of melanoma differentiation-associated gene-7/interleukin 24 (mda-7/IL-24) in invasive primary human glioblastoma multiforme (GBM) cells. Additionally, a method is described to augment the efficacy of adenoviral delivery of mda-7/IL-24 in these cells. HDACIs synergized with melanoma differentiation-associated (MDA)-7/IL-24 killing GBM cells. Enhanced lethality correlated with increased autophagy that was dependent on the expression of ceramide synthase 6. HDACIs interacted with MDA-7/IL-24 prolonging generation of reactive oxygen species and Ca(2+). Quenching of reactive oxygen species and Ca(2+) blocked HDACI and MDA-7/IL-24 killing. In vivo MDA-7/IL-24 prolonged the survival of animals carrying orthotopic tumors, and HDACIs enhanced survival further. A serotype 5/3 adenovirus more effectively delivers mda-7/IL-24 to GBM tumors than a serotype 5 virus. Hence, we constructed a serotype 5/3 adenovirus that conditionally replicates in tumor cells expressing MDA-7/IL-24, in which the adenoviral early region 1A (E1A) gene was driven by the cancer-specific promoter progression elevated gene-3 [Ad.5/3 (INGN 241)-PEG-E1A-mda-7; also called Ad.5/3-CTV (cancer terminator virus)]. Ad.5/3-CTV increased the survival of mice carrying GBM tumors to a significantly greater extent than did a nonreplicative virus Ad.5/3-mda-7. Ad.5/3-CTV exhibited no toxicity in the brains of Syrian hamsters. Collectively our data demonstrate that HDACIs enhance MDA-7/IL-24 lethality, and adenoviral delivery of mda-7/IL-24 combined with tumor-specific viral replication is an effective preclinical GBM therapeutic.

Li J, Wang Y, Zhu Y, Oupický D
Recent advances in delivery of drug-nucleic acid combinations for cancer treatment.
J Control Release. 2013; 172(2):589-600 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Cancer treatment that uses a combination of approaches with the ability to affect multiple disease pathways has been proven highly effective in the treatment of many cancers. Combination therapy can include multiple chemotherapeutics or combinations of chemotherapeutics with other treatment modalities like surgery or radiation. However, despite the widespread clinical use of combination therapies, relatively little attention has been given to the potential of modern nanocarrier delivery methods, like liposomes, micelles, and nanoparticles, to enhance the efficacy of combination treatments. This lack of knowledge is particularly notable in the limited success of vectors for the delivery of combinations of nucleic acids with traditional small molecule drugs. The delivery of drug-nucleic acid combinations is particularly challenging due to differences in the physicochemical properties of the two types of agents. This review discusses recent advances in the development of delivery methods using combinations of small molecule drugs and nucleic acid therapeutics to treat cancer. This review primarily focuses on the rationale used for selecting appropriate drug-nucleic acid combinations as well as progress in the development of nanocarriers suitable for simultaneous delivery of drug-nucleic acid combinations.

Zhuo B, Wang R, Yin Y, et al.
Adenovirus arming human IL-24 inhibits neuroblastoma cell proliferation in vitro and xenograft tumor growth in vivo.
Tumour Biol. 2013; 34(4):2419-26 [PubMed] Related Publications
Data have increasingly shown that interlukin-24 (IL-24) has growth suppression activity and can induce apoptosis in a broad spectrum of tumor cells. However, the therapeutic effect of IL-24 on human neuroblastoma has rarely been explored. In this study, we used a human neuroblastoma cell line (SH-SY5Y) to reveal the effect of adenovirus-mediated IL-24 (Ad-IL24) gene therapy for neuroblastoma. We showed that Ad-IL24 effectively inhibited the proliferation of SH-SY5Y cells in vitro by conspicuously inducing apoptosis. To further explore the molecular mechanism by which Ad-IL24 induced apoptosis in SH-SY5Y tumor cells, we found that Ad-IL24 increased the expression of Bax and promoted the activation of caspase-3, while decreasing Bcl-2 levels. We also demonstrated that Ad-IL24 significantly inhibited tumor growth in vivo in a xenograft neuroblastoma tumor in athymic nude mice. In summary, Ad-IL24 overexpression exerted potent antitumor activity via inducing apoptosis in neuroblastoma cells. Therefore, IL-24 has the potential to serve as an agent for gene therapy in the treatment of neuroblastoma.

Frewer NC, Ye L, Sun PH, et al.
Potential implication of IL-24 in lymphangiogenesis of human breast cancer.
Int J Mol Med. 2013; 31(5):1097-104 [PubMed] Related Publications
Lymphangiogenesis is involved in the dissemination of malignant cells from solid tumours to regional lymph nodes and possibly to various distant sites. Lymphangiogenesis is regulated by vascular endothelial growth factor (VEGF)-C and VEGF-D. Interleukin (IL)-24 is known as a cytokine with potent antitumour and tumour-suppressive activity which functions through its receptor (IL-22R). Expression of IL-24 has been shown to be reduced in breast cancer, and the reduced expression is associated with lymphatic metastases and a poor prognosis. However, the involvement of IL-24 in lymphangiogenesis during lymphatic metastasis remains unclear. The aim of the present study was to determine whether there is an association between IL-24, IL-22R and lymphangiogenic factors and markers in breast cancer. Analysis of IL-24, IL-22R and lymphangiogenic factors in malignant breast tissue samples (n=127) revealed a correlation between increased expression of lymphangiogenic markers (podoplanin, Prox-1 and LYVE-1) and reduced levels of IL-24 and IL-22R. Samples stained with a high degree of positivity for lymphangiogenic factors and markers whereas staining for IL-24 was weak. In vitro assays showed that the average perimeter length of microtubules formed by endothelial cells treated with IL-24 was significantly reduced compared to the control. The growth of endothelial cells was significantly reduced when exposed to a high concentration of IL-24 (250 ng/ml). Treatment of HECV cells with IL-24 resulted in significantly reduced expression of VEGF-C (P<0.05) and VEGF-D (P<0.001). In conclusion, reduced expression of IL-24 and IL-22R in breast cancer is correlated with increased expression of specific lymphangiogenic markers. IL-24 suppressed in vitro growth and microtubule formation of endothelial cells. IL-24 may downregulate the expression of lymphangiogenic markers and factors although further research is required. This suggests that IL-24 plays a profound role in suppressing tumour lymphangiogenesis, thereby, reducing the likelihood of cancer metastasis via the lymphatic route.

Li YJ, Liu G, Li Y, et al.
mda-7/IL-24 expression inhibits breast cancer through upregulation of growth arrest-specific gene 3 (gas3) and disruption of β1 integrin function.
Mol Cancer Res. 2013; 11(6):593-603 [PubMed] Related Publications
Melanoma differentiation-associated gene (MDA)-7)/interleukin (IL)-24, a member of the IL-10 family of cytokines, inhibits growth of various human cancer cells, yet the underlying mechanism is largely unknown. Here, we report that mda-7/IL-24 efficiently suppresses the development of rat mammary tumors in vivo. Microarray analysis for genes differentially expressed in rat mammary tumor cells overexpressing MDA-7/IL-24 compared with those that do not express this cytokine identified growth arrest-specific gene-3 (gas3) as a target for mda-7/IL-24. Upregulation of gas3 by mda-7/IL-24 was STAT3 dependent. Induction of gas3 inhibited attachment and proliferation of tumor cells in vitro and in vivo by inhibiting the interaction of β1 integrin with fibronectin. A mutated GAS3, which is unable to bind β1 integrin, was also unable to inhibit fibronectin-mediated attachment and cell growth both in adherent and suspension cultures, suggesting that GAS3 exerts its effects through interaction with and regulation of β1 integrin. Thus, mda-7/IL-24 inhibits breast cancer growth, at least in part, through upregulation of GAS3 and disruption of β1 integrin function. Importantly, the expression of the mda-7/IL-24 receptor, IL-20R1, is highly correlated with GAS3 expression in human breast cancer (P = 1.02 × 10(-9)), and the incidence of metastases is significantly reduced in patients with HER2(+) breast cancer expressing high-levels of IL-20R1. Together, our results identify a novel MDA-7/IL-24-GAS3-β1integrin-fibronectin signaling pathway that suppresses breast cancer growth and can be targeted for therapy.

Weiss R, Sachet M, Zinngrebe J, et al.
IL-24 sensitizes tumor cells to TLR3-mediated apoptosis.
Cell Death Differ. 2013; 20(6):823-33 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Interleukin-24 (IL-24), a member of the IL-10 cytokine family whose physiological function remains largely unknown, has been shown to induce apoptosis when expressed in an adenoviral background. It is yet little understood, why IL-24 alone induced apoptosis only in a limited number of tumor cell lines. Analyzing an influenza A virus vector expressing IL-24 for its oncolytic potential revealed enhanced pro-apoptotic activity of the chimeric virus compared with virus or IL-24 alone. Interestingly, IL-24-mediated enhancement of influenza-A-induced apoptosis did not require viral replication but critically depended on toll-like receptor 3 (TLR3) and caspase-8. Immunoprecipitation of TLR3 showed that infection by influenza A virus induced formation of a TLR3-associated signaling complex containing TRIF, RIP1, FADD, cFLIP and pro-caspase-8. Co-administration of IL-24 decreased the presence of cFLIP in the TLR3-associated complex, converting it into an atypical, TLR3-associated death-inducing signaling complex (TLR3 DISC) that induced apoptosis by enabling caspase-8 activation at this complex. The sensitizing effect of IL-24 on TLR3-induced apoptosis, mediated by influenza A virus or the TLR3-specific agonist poly(I:C), was also evident on tumor spheroids. In conclusion, rather than acting as an apoptosis inducer itself, IL-24 sensitizes cancer cells to TLR-mediated apoptosis by enabling the formation of an atypical DISC which, in the case of influenza A virus or poly(I:C), is associated with TLR3.

Jiang G, Jiang AJ, Cheng Q, et al.
A dual-regulated oncolytic adenovirus expressing interleukin-24 sensitizes melanoma cells to temozolomide via the induction of apoptosis.
Tumour Biol. 2013; 34(2):1263-71 [PubMed] Related Publications
Malignant melanoma is one of the most lethal and aggressive human malignancies. Suppressed apoptosis and extraordinary invasiveness are the distinctive features that contribute to malignant melanoma. The alkylating agent temozolomide (TMZ) is one of the most effective single chemotherapeutic agents for patients with malignant melanoma, but resistance develops quickly and with high frequency. We constructed a dual-regulated oncolytic adenovirus expressing interleukin 24 (IL-24) gene (Ki67-ZD55-IL-24) by utilizing the Ki67 promoter to replace the native viral promoter of E1A gene. We investigated whether a combination of Ki67-ZD55-IL-24-mediated gene virotherapy and chemotherapy using TMZ produces increased cytotoxicity against human melanoma cells via the induction of apoptosis. Our data indicate that this novel strategy thus holds promising potentials for further developing an effective approach to treat malignant melanoma.

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