SIRT1 Downregulation Directs Mitochondrial Hyperfusion for Inhibition of Apoptosis in Cisplatin-Treated Oral Cancer Cells

Abstract

SIRT1 (NAD-dependent protein deacetylase sirtuin-1), a class III HDAC acting as a tumor suppressor gene, is downregulated in oral cancer cells. Optimal doses of cisplatin (CDDP) are found to downregulate SIRT1 expression advocating the mechanism of drug resistance. SIRT1 downregulation orchestrates inhibition of DNM1L-mediated mitochondrial fission, subsequently leading to the formation of hyperfused mitochondrial networks. The hyperfused mitochondrial networks preserve the release of cytochrome C by stabilizing the mitochondrial inner membrane cristae (formation of mitochondrial nucleoids clustering mimicking mito-bulb like structures) to inhibit apoptosis. Overexpression of SIRT1 reverses the mitochondrial hyperfusion by initiating DNM1L-FIS1-regulated mitochondrial fission. In the overexpression conditions, inhibition of mitochondrial hyperfusion and nucleoid clustering (mito-bulbs) facilitates the cytoplasmic release of cytochrome C to induce apoptosis in oral cancer cells. Further, low-dose priming with gallic acid (GA), a bio-active SIRT1 activator, also nullifies CDDP-mediated inhibition of apoptosis by reducing mito-bulb formation. When SIRT1 is knocked down from the GA-primed cells, the activation of apoptosis is found to be reversed. Similarly, SIRT1 overexpression in the CDDP resistance oral cancer polyploid giant cancer cells (PGCCs) re-sensitizes the cells to apoptosis. Further, synergistically treated with CDDP, gallic acid induces apoptosis in the oral cancer PGCCs by inhibiting mitochondrial hyperfusion.