Insights into the Mechanisms of Action of MDA-7/IL-24: A Ubiquitous Cancer-Suppressing Protein

Modi, Jinkal; Roy, Abhishek; Pradhan, Anjan K.; Kumar, Amit; Talukdar, Sarmistha; Bhoopathi, Praveen; Maji, Santanu; Padmanabhan, M.; Rosa, Daniel Sanchez De La; Li, Jiong; Guo, Chunqing; Subler, Mark A.; Windle, Jolene J.; Cavenee, Webster K.; Sarkar, Devanand; Wang, Xiangyang; Das, Swadesh K.; Emdad, Luni; Fisher, Paul B.

doi:10.3390/ijms23010072

Cited by 8 publications

(7 citation statements)

References 153 publications

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“…Moreover, WX8 together with AdV‐ IL24 overexpression was more than twice as effective in terminating PIKFYVE‐sensitive melanoma cells as either agent alone. Accordingly, PIKFYVE inhibitors could complement the ability of ectopically expressed IL24 to induce cancer‐specific cell death in patients with advanced cancers (discussed in [ 74 , 75 ]).…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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

Roy,

Chakraborty,

DePamphilis

2024

Molecular Oncology

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“…The present study demonstrated that PAI-1 is a key molecule that supressed IL-24 expression in MLS cells. IL-24 is a unique antitumor cytokine with various tumor-suppressive activities, including the suppression of tumor growth, invasion, and metastasis (33). IL-24 regulates key proteins involved in the regulation of endoplasmic reticulum stress and mitochondrial function, and induces apoptosis with toxic autophagy in diverse malignant tumor cells (33,34).…”

Section: Discussionmentioning

confidence: 99%

Suppression of antitumor cytokine IL‑24 by PRG4 and PAI‑1 may promote myxoid liposarcoma cell survival

2023

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Suppression of the antitumor cytokine interleukin-24 (IL-24) is critical for the survival of myxoid liposarcoma (MLS) cells. It has been previously demonstrated by the authors that an MLS-specific chimeric oncoprotein, translocated in liposarcoma-CCAAT/enhancer-binding protein homologous protein (TLS-CHOP), supresses IL24 mRNA expression via induction of proteoglycan 4 (PRG4) to sustain MLS cell proliferation. However, IL-24 has also been revealed to be suppressed by the ubiquitin-proteasome system in human ovarian and lung cancer cells. Therefore, the aim of the present study was to elucidate the mechanism of IL-24 suppression in MLS cells. The results revealed that the proteasome inhibitor, MG-132, induced cell death in MLS cells in vitro; this effect was reduced following IL-24 knockdown. This indicated that proteasomal degradation of IL-24 may be an important process for MLS cell survival. In addition, it was also previously revealed by the authors that knockdown of plasminogen activator inhibitor-1 (PAI-1), a TLS-CHOP downstream molecule, suppressed the growth of MLS cells, thus instigating the investigation of the effect of PAI-1 on IL-24 expression in MLS cells. Double knockdown of PAI-1 and IL-24 negated the growth-suppressive effect of PAI-1 single knockdown in MLS cells. Interestingly, PAI-1 single knockdown did not increase the mRNA expression of IL24, but it did increase the protein abundance of IL-24, indicating that PAI-1 suppressed IL-24 expression by promoting its proteasomal degradation. Moreover, treatment of MLS cells with a PAI-1 inhibitor, TM5275, induced IL-24 protein expression and apoptosis. Collectively, the results of the present as well as previous studies indicated that IL-24 expression may be suppressed at the transcriptional level by PRG4 and at the protein level by PAI-1 in MLS cells. Accordingly, PAI-1 may represent an effective therapeutic target for MLS treatment.

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“…Notably, among the upregulated cytokine genes, IL24 exhibited the most substantial increase following GFP-MYPOP expression. IL24 encodes the well-studied tumor suppressive interleukin-24, also known as melanoma differentiation association protein-7 (MDA-7) [34][35][36][37] . Moreover, our analysis identi ed several well-characterized proto-oncogenes, such as MYC, FOS, and JUN, among the downregulated candidates (Supplementary Table 1).…”

Section: Mypop Modulates Gene Expression Of Cytokines and Cell Cycle ...mentioning

confidence: 99%

“…These cytokines play crucial roles in wound healing processes and in the tumor microenvironment (TME) 66,67 . Hereby, of particular interest is the well-studied tumor suppressor cytokine IL-24, a member of the IL-10 family also called MDA-7, which among other functions in cell differentiation, host defense, and wound healing 68,69 was shown to induce apoptosis in tumor cells, as demonstrated in a phase I clinical trial 34,37,70 . This implies that MYPOP blocks multiple steps of the cell cycle by silencing oncogenes, modulating cell cycle regulators and induction of IL-24, which might collectively contribute to the inhibition of cell growth.…”

Section: Mypop's Impact On Gene Expression Of Cell Cycle Regulatorsmentioning

confidence: 99%

The MYB-related transcription factor MYPOP acts as a selective regulator of cancer cell growth

Florin,

Strunk,

Hüppner

et al. 2024

Preprint

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The MYB-related transcription factor and partner of profilin (MYPOP or p42POP) is a ubiquitously expressed and understudied protein, recently discovered in restricting oncogenic human papillomaviruses (HPV) and suggested as a tumor suppressor. In this study, we investigate the role of MYPOP on cancer cells. At supra-physiological levels, induced by both plasmid DNA- and messenger RNA-mediated gene transfer, MYPOP emerges as a potent tumor growth inhibitor, capable of inducing cancer cell death while sparing normal cells. Using HPV-transformed cervical cancer cells and normal human epidermal keratinocytes, cell behavior assessments as well as transcriptome analysis revealed MYPOP's specific anti-proliferative and death-inducing impact on cancer cells. We found MYPOP capable of silencing viral and human oncogenes including E6, E7, and MYC, and of triggering the release of the cancer-killing cytokine interleukin-24. Extending our research to murine Mypop, we observed anti-proliferative effects in mouse melanoma and colorectal cancer cells. Collectively, our findings underscore MYPOP's potential as a selective tumor suppressor in both human and mouse cancer cells, opening a promising avenue for future in vivo studies.

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Insights into the Mechanisms of Action of MDA-7/IL-24: A Ubiquitous Cancer-Suppressing Protein

Cited by 8 publications

References 153 publications

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

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

Suppression of antitumor cytokine IL‑24 by PRG4 and PAI‑1 may promote myxoid liposarcoma cell survival

The MYB-related transcription factor MYPOP acts as a selective regulator of cancer cell growth

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