Cell Death and Disease (Apr 2022)

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

  • Caterina Vianello,
  • Veronica Cocetta,
  • Daniela Catanzaro,
  • Gerald W Dorn,
  • Angelo De Milito,
  • Flavio Rizzolio,
  • Vincenzo Canzonieri,
  • Erika Cecchin,
  • Rossana Roncato,
  • Giuseppe Toffoli,
  • Vincenzo Quagliariello,
  • Annabella Di Mauro,
  • Simona Losito,
  • Nicola Maurea,
  • Cono Scaffa,
  • Gabriele Sales,
  • Luca Scorrano,
  • Marta Giacomello,
  • Monica Montopoli

DOI
https://doi.org/10.1038/s41419-022-04741-9
Journal volume & issue
Vol. 13, no. 4
pp. 1 – 14

Abstract

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Abstract 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.