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http://hdl.handle.net/2080/3919
Title: | CLU (clusterin) and PPARGC1A/PGC1α Coordinately Control Mitophagy and Mitochondrial Biogenesis for Oral Cancer Cell Survival |
Authors: | Praharaj, Prakash P. Bhutia, Sujit Kumar |
Keywords: | Clusterin mitochondrial biogenesis mitophagy mitophagy-associated cell death PPARGC1A/PGC1α |
Issue Date: | Jan-2023 |
Citation: | 42nd Annual Conference of IACR (IACR 2023), ACTREC, Mumbai, 12-15 January 2023 |
Abstract: | Mitophagy involves the selective elimination of defective mitochondria during chemotherapeutic stress to maintain mitochondrial homeostasis and sustain cancer growth. Here, we showed that CLU (clusterin) is localized to mitochondria to induce mitophagy controlling mitochondrial damage in oral cancer cells. Moreover, overexpression and knockdown of CLU establish its mitophagy-specific role, where CLU coordinately interacts with BAX and LC3 forming a tri-complex to clear damaged mitochondria in response to cisplatin treatment. Interestingly, CLU triggers class III phosphatidylinositol 3-kinase (PtdIns3K) activity around damaged mitochondria, and inhibition of mitophagic flux causes the accumulation of excessive mitophagosomes causing reactive oxygen species (ROS)-dependent apoptosis during cisplatin treatment in oral cancer cells. In parallel, we determined that PPARGC1A/PGC1α (PPARG coactivator 1 alpha) activates mitochondrial biogenesis during CLU-induced mitophagy to maintain the mitochondrial pool. Intriguingly, PPARGC1A inhibition through small interfering RNA (siPPARGC1A) and pharmacological inhibitor (SR-18292) treatment counteracts CLU-dependent cytoprotection leading to mitophagy-associated cell death. Furthermore, co-treatment of SR-18292 with cisplatin synergistically suppresses tumor growth in oral cancer xenograft models. In conclusion, CLU and PPARGC1A are essential for sustained cancer cell growth by activating mitophagy and mitochondrial biogenesis, respectively, and their inhibition could provide better therapeutic benefits against oral cancer |
Description: | Copyright belongs to proceeding publisher |
URI: | http://hdl.handle.net/2080/3919 |
Appears in Collections: | Conference Papers |
Files in This Item:
File | Description | Size | Format | |
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2022_ACTREC_SKBhutia_Clusterin.pdf | 1.46 MB | Adobe PDF | View/Open |
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