PIKFYVE inhibitors trigger interleukin-24-dependent cell death of autophagy-dependent melanoma
Ajit Roy1, Arup R Chakraborty1, Melvin L DePamphilis1
1National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, MD, USA.
Abstract:
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.
Insights
PIKFYVE inhibitors selectively kill cancer cells by disrupting lysosome function and inducing endoplasmic reticulum stress via the IL24 pathway. This targeted approach offers a promising therapeutic strategy for melanoma treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- 1-phosphatidylinositol 3-phosphate 5-kinase (PIKFYVE) inhibitors disrupt lysosome homeostasis.
- This disruption selectively eliminates autophagy-dependent cancer cells while sparing normal cells.
- The precise mechanism of PIKFYVE inhibitor-induced cell death requires elucidation.
Purpose of the Study:
- To investigate the molecular mechanism by which PIKFYVE inhibition leads to cancer cell death.
- To compare the cellular response to PIKFYVE inhibitors in melanoma cells versus normal fibroblasts.
- To identify key pathways and molecules involved in selective cancer cell termination.
Main Methods:
- Comparative analysis of autophagy-dependent melanoma cells and normal foreskin fibroblasts.
- RNA sequence profiling to identify differentially expressed genes.
- Biochemical and genetic analyses, including gene expression and ablation studies.
- In vivo studies using tumor xenografts.
Main Results:
- PIKFYVE inhibitors selectively upregulate endoplasmic reticulum (ER) stress and interleukin-24 (IL24) expression in melanoma cells.
- IL24 upregulation is mediated by the DDIT3/CHOP/CEBPz transcription factor within the PERK-dependent ER-stress pathway.
- Ectopic IL24 expression induces cell death in melanoma cells, while IL24 gene ablation prevents it.
- PIKFYVE inhibitors selectively induce IL24-dependent ER-stress and cell death in sensitive melanoma cells, unlike non-selective ER stressors.
Conclusions:
- PIKFYVE inhibitors offer a targeted mechanism for cancer therapy by inducing selective ER stress and cell death.
- The PIKFYVE-IL24-ER stress axis represents a novel therapeutic vulnerability in melanoma.
- Combined PIKFYVE inhibition and IL24 expression show additive effects, highlighting their therapeutic potential for melanoma treatment.
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