Cisplatin resistance can be curtailed by blunting Bnip3-mediated mitochondrial autophagy

• Published in: Cell death & disease 2022-04, Vol.13 (4), p.398-398, Article 398
• Main Authors: Vianello, Caterina, Cocetta, Veronica, Catanzaro, Daniela, Dorn, Gerald W, De Milito, Angelo, Rizzolio, Flavio, Canzonieri, Vincenzo, Cecchin, Erika, Roncato, Rossana, Toffoli, Giuseppe, Quagliariello, Vincenzo, Di Mauro, Annabella, Losito, Simona, Maurea, Nicola, Scaffa, Cono, Sales, Gabriele, Scorrano, Luca, Giacomello, Marta, Montopoli, Monica
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/109; 13/2; 13/31; 13/51; 14; 14/1; 14/19; 14/28; 14/33; 14/34; 14/63; 38; 38/77; 38/89; 38/90; 631/67/1059/2326; 631/80/39/2348; 82/29; Antibodies; Antineoplastic Agents - therapeutic use; Autophagy; Autophagy - genetics; Biochemistry; Biomedical and Life Sciences; BNIP3 protein; Bone cancer; Bone Neoplasms - drug therapy; Bone Neoplasms - genetics; Bone Neoplasms - metabolism; Cancer research; Carcinoma, Ovarian Epithelial - drug therapy; Cell Biology; Cell Culture; Cell death; Cell Line, Tumor; Cervical cancer; Cervix; Chemotherapy; Cisplatin; Cisplatin - therapeutic use; Cytochrome c; Cytology; Cytotoxicity; Drug Resistance, Neoplasm - genetics; Endoplasmic reticulum; Female; Humans; Hypoxia-inducible factor 1a; Immunology; Life Sciences; Medicin och hälsovetenskap; Membrane Proteins - metabolism; Mitochondria; Mitochondria - metabolism; Molecular modelling; Osteosarcoma; Osteosarcoma - drug therapy; Osteosarcoma - genetics; Osteosarcoma - metabolism; Ovarian cancer; Ovarian carcinoma; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Platinum; Proto-Oncogene Proteins - metabolism; Tumor cell lines; Tumors
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-022-04741-9

Cisplatin (CDDP) is commonly used to treat a multitude of tumors including sarcomas, ovarian and cervical cancers. Despite recent investigations allowed to improve chemotherapy effectiveness, the molecular mechanisms underlying the development of CDDP resistance remain a major goal in cancer research. Here, we show that mitochondrial morphology and autophagy are altered in different CDDP resistant cancer cell lines. In CDDP resistant osteosarcoma and ovarian carcinoma, mitochondria are fragmented and closely juxtaposed to the endoplasmic reticulum; rates of mitophagy are also increased. Specifically, levels of the mitophagy receptor BNIP3 are higher both in resistant cells and in ovarian cancer patient samples resistant to platinum-based treatments. Genetic BNIP3 silencing or pharmacological inhibition of autophagosome formation re-sensitizes these cells to CDDP. Our study identifies inhibition of BNIP3-driven mitophagy as a potential therapeutic strategy to counteract CDDP resistance in ovarian carcinoma and osteosarcoma. BNIP3-mediated mitochondrial clearance as a mechanism underlying resistance to cisplatin CDDP induces the stabilization of HIF-1α that leads to the expression of its target gene BNIP3. BNIP3 promotes autophagy of mitochondria by increasing their fission and degradation rates. This process ultimately boosts the ability of resistant cancer cells to escape CDDP cytotoxicity by eliminating one of its main targets, mitochondria, from which cytochrome c is released to initiate cell death. While BNIP3 expression could be a new prognostic factor to predict the chemotherapy responsiveness of cancer patients, targeting mitophagy could be a new therapeutic approach to overcome platinum resistance. We used BioRender Software (BioRender.com) to draw the schematic picture.