Targeting inhibition of K-ras enhances Ad.mda-7-induced growth suppression and apoptosis in mutant K-ras colorectal cancer cells

Lebedeva, Irina V.; Su, Zao-zhong; Emdad, Luni; Kolomeyer, Anton M.; Sarkar, Devanand; Kitada, Shinichi; Waxman, Samuel; Reed, John C.; Fisher, Paul B.

doi:10.1038/sj.onc.1209813

Cited by 27 publications

(39 citation statements)

References 49 publications

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“…Such an explanation would also be compatible with the fact that by blocking one single pathway, induced by MDA-7/IL-24, it is possible to block the killing effect. ROS, key mediators of MDA-7/IL-24 effects, have been shown to have differential effects on cancer cells versus normal cells (12,13,28). Multiple studies have demonstrated that the basal ROS level in cancer cells is higher than that in normal cells (36).…”

Section: Discussionmentioning

confidence: 99%

“…Cancer cells, DU-145, A549, PC-3, HO-1, and HeLa, and normal cells, FM516-SV immortalized normal human melanocytes, P69 immortalized normal human prostate epithelial cells, and PHFA, were cultured as described (11)(12)(13). MTT assays and apoptosis assays were performed by flow cytometry (11)(12)(13)18). For analysis of ROS production, cells were stained with DCFH-DA and analyzed by flow cytometry (12).…”

Section: Methodsmentioning

confidence: 99%

“…Based on its structure, chromosomal location, and biochemical properties, mda-7 has been classified as a member of the IL-10 family of cytokines that includes IL-10, IL-19, IL-20, IL-22, and IL-26 and has been redesignated IL-24 (3,4). When expressed at supraphysiological levels, by means of an adenoviral (Ad) expression system (Ad.mda-7), MDA-7/ IL-24 induces growth suppression and apoptosis in a broad spectrum of human cancer cells, including those from melanoma, malignant glioma, fibrosarcoma, and carcinomas of the breast, cervix, colon, rectum, liver, lung, ovary, and prostate, without exerting any deleterious effects on their normal counterparts (5)(6)(7)(8)(9)(10)(11)(12)(13). A phase I trial evaluating Ad.mda-7 (INGN 241) activity by intratumoral injection in patients with advanced solid tumors was performed, indicating that mda-7/IL-24 was safe and could induce as much as 70% apoptosis in tumors after a single injection of recombinant virus and that multiple injections elicited clinical responses (14)(15)(16).…”

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confidence: 99%

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Autocrine regulation of mda -7/IL-24 mediates cancer-specific apoptosis

Sauane¹,

Gupta³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

117

153

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A noteworthy aspect of melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) as a cancer therapeutic is its ability to selectively kill cancer cells without harming normal cells. Intracellular MDA-7/IL-24 protein, generated from an adenovirus expressing mda-7/IL-24 (Ad.mda-7), induces cancerspecific apoptosis by inducing an endoplasmic reticulum (ER) stress response. Secreted MDA-7/IL-24 protein, generated from cells infected with Ad.mda-7, induces growth inhibition and apoptosis in surrounding noninfected cancer cells but not in normal cells, thus exerting an anti-tumor ''bystander'' effect. The present studies reveal a provocative finding that recombinant MDA-7/IL-24 protein can robustly induce expression of endogenous mda-7/IL-24, which generates the signaling events necessary for bystander killing. To evaluate the mechanism underlying this positive autocrine feedback loop, we show that MDA-7/IL-24 protein induces stabilization of its own mRNA without activating its promoter. Furthermore, this posttranscriptional effect depends on de novo protein synthesis. As a consequence of this autocrine feedback loop MDA-7/IL-24 protein induces sustained ER stress as evidenced by expression of ER stress markers (BiP/GRP78, GRP94, GADD153, and phosphoeIF2␣) and reactive oxygen species production, indicating that both intracellular and secreted proteins activate similar signaling pathways to induce apoptosis. Thus, our results clarify the molecular mechanism by which secreted MDA-7/IL-24 protein (generated from Ad.mda-7-infected cells) exerts cancer-specific killing.bystander antitumor activity ͉ endoplasmic reticulum stress ͉ reactive oxygen species ͉ mRNA stabalization ͉ cancer-specific killing

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Autocrine regulation of mda -7/IL-24 mediates cancer-specific apoptosis

Sauane¹,

Gupta³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

117

153

View full text Add to dashboard Cite

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“…Viability assays were performed as previously described (Lebedeva et al, 2007). Briefly, cells were seeded in 96-well plates 5 Â 10 3 cells/well for PHFA cells or 1.5 Â 10 3 cells/well for other cell lines) and infected the next day with different adenoviruses.…”

Section: Mtt Viability Assaysmentioning

confidence: 99%

“…Annexin V binding assay, hypodiploidy analysis and caspase activity assay Annexin V binding assay and hypodiploidy analysis were performed as previously described (Lebedeva et al, 2007). Caspase 3, 7 and 9 activities in PHFA were measured using Caspases-Glo 3/7 Assay and Caspase-Glo 9 Assay kits (Promega, Madison, MI, USA) according to the manufacturer's instructions.…”

Section: Preparation Of Cell Extracts and Western Blotting Analysismentioning

confidence: 99%

Astrocyte elevated gene-1 activates cell survival pathways through PI3K-Akt signaling

et al. 2007

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PIKFYVE inhibitors trigger interleukin‐24‐dependent cell death of autophagy‐dependent melanoma

Roy,

Chakraborty,

DePamphilis

2024

Molecular Oncology

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Inhibitors specifically targeting the 1‐phosphatidylinositol 3‐phosphate 5‐kinase (PIKFYVE) disrupt lysosome homeostasis, thereby selectively terminating autophagy‐dependent human cancer cells in vivo as well as in vitro without harming the viability of nonmalignant cells. To elucidate the mechanism by which PIKFYVE inhibition induces cell death, autophagy‐dependent melanoma cells were compared with normal foreskin fibroblasts. RNA sequence profiling suggested that PIKFYVE inhibitors upregulated an endoplasmic reticulum (ER) stress response involving interleukin‐24 (IL24; also known as MDA7) selectively in melanoma cells. Subsequent biochemical and genetic analyses confirmed these results and extended them to tumor xenografts in which tumor formation and expansion were inhibited. IL24 expression was upregulated by the DDIT3/CHOP/CEBPz transcription factor, a component of the PERK‐dependent ER‐stress response. Ectopic expression of IL24‐induced cell death in melanoma cells, but not in foreskin fibroblasts, whereas ablation of the IL24 gene in melanoma cells prevented death. IL24 upregulation was triggered specifically by PIKFYVE inhibition. Thus, unlike thapsigargin and tunicamycin, which induce ER‐stress indiscriminately, PIKFYVE inhibitors selectively terminated PIKFYVE‐sensitive melanoma by inducing IL24‐dependent ER‐stress. Moreover, induction of cell death by a PIKFYVE inhibitor together with ectopic expression of IL24 protein was cumulative, thereby confirming the therapeutic potential of PIKFYVE inhibitors in the treatment of melanoma.

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Targeting inhibition of K-ras enhances Ad.mda-7-induced growth suppression and apoptosis in mutant K-ras colorectal cancer cells

Cited by 27 publications

References 49 publications

Autocrine regulation of mda -7/IL-24 mediates cancer-specific apoptosis

Autocrine regulation of mda -7/IL-24 mediates cancer-specific apoptosis

Astrocyte elevated gene-1 activates cell survival pathways through PI3K-Akt signaling

PIKFYVE inhibitors trigger interleukin‐24‐dependent cell death of autophagy‐dependent melanoma

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