SIRT1 inhibits mitochondrial hyperfusion associated mito-bulb formation to sensitize oral cancer cells for apoptosis in a mtROS-dependent signalling pathway

SIRT1 (NAD-dependent protein deacetylase sirtuin-1), a class III histone deacetylase acting as a tumor suppressor gene, is downregulated in oral cancer cells. Non-apoptotic doses of cisplatin (CDDP) downregulate SIRT1 expression advocating the mechanism of drug resistance. SIRT1 downregulation orche...

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Bibliographic Details
Published in:Cell death & disease 2023-11, Vol.14 (11), p.732-732, Article 732
Main Authors: Patra, Srimanta, Singh, Amruta, Praharaj, Prakash P., Mohanta, Nitish K., Jena, Mrutyunjay, Patro, Birija S., Abusharha, Ali, Patil, Shankargouda, Bhutia, Sujit K.
Format: Article
Language:English
Subjects:
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82/1
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Antibodies
Apoptosis
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Culture
Cisplatin
Cristae
Cytochrome c
Down-regulation
Drug resistance
Gallic acid
Histone deacetylase
Immunology
Life Sciences
Mitochondria
Oral cancer
Polyploidy
Signal transduction
SIRT1 protein
Superoxide
Tumor suppressor genes
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Summary:SIRT1 (NAD-dependent protein deacetylase sirtuin-1), a class III histone deacetylase acting as a tumor suppressor gene, is downregulated in oral cancer cells. Non-apoptotic doses of cisplatin (CDDP) 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 (CYCS) by stabilizing the mitochondrial inner membrane cristae (formation of mitochondrial nucleoid clustering mimicking mito-bulb like structures) and reducing the generation of mitochondrial superoxide to inhibit apoptosis. Overexpression of SIRT1 reverses the mitochondrial hyperfusion by initiating DNM1L-regulated mitochondrial fission. In the overexpressed cells, inhibition of mitochondrial hyperfusion and nucleoid clustering (mito-bulbs) facilitates the cytoplasmic release of CYCS along with an enhanced generation of mitochondrial superoxide for the subsequent induction of apoptosis. Further, low-dose priming with gallic acid (GA), a bio-active SIRT1 activator, nullifies CDDP-mediated apoptosis inhibition by suppressing mitochondrial hyperfusion. In this setting, SIRT1 knockdown hinders apoptosis activation in GA-primed oral cancer cells. Similarly, SIRT1 overexpression in the CDDP resistance oral cancer-derived polyploid giant cancer cells (PGCCs) re-sensitizes the cells to apoptosis. Interestingly, synergistically treated with CDDP, GA induces apoptosis in the PGCCs by inhibiting mitochondrial hyperfusion.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-023-06232-x