Cisplatin resistance can be curtailed by blunting Bnip3-mediated mitochondrial autophagy.
Cisplatin resistance can be curtailed by blunting Bnip3-mediated mitochondrial autophagy.
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DOI：
10.1038/s41419-022-04741-9
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发表时间：
2022-04-22
影响因子：
9
通讯作者：
Montopoli, Monica
中科院分区：
文献类型：
--
作者：
Vianello, Caterina;Cocetta, Veronica;Catanzaro, Daniela;Dorn, Gerald W. I. I. I. I.;De Milito, Angelo;Rizzolio, Flavio;Canzonieri, Vincenzo;Cecchin, Erika;Roncato, Rossana;Toffoli, Giuseppe;Quagliariello, Vincenzo;Di Mauro, Annabella;Losito, Simona;Maurea, Nicola;Cono, Scaffa;Sales, Gabriele;Scorrano, Luca;Giacomello, Marta;Montopoli, Monica
顺铂（CDDP）通常用于治疗多种肿瘤，包括肉瘤、卵巢癌和宫颈癌。尽管最近的研究允许提高化疗的有效性，但CDDP耐药性发展的分子机制仍然是癌症研究的主要目标。在这里，我们发现线粒体形态和自噬在不同的CDDP耐药癌细胞系中发生了改变。在CDDP耐药的骨肉瘤和卵巢癌中，线粒体破碎并与内质网紧密并列;线粒体自噬率也增加。具体地说，线粒体自噬受体BNIP 3的水平在耐药细胞和对铂类治疗耐药的卵巢癌患者样本中均较高。遗传BNIP 3沉默或自噬体形成的药理学抑制使这些细胞对CDDP重新敏感。我们的研究确定了抑制BNIP 3驱动的线粒体自噬作为一种潜在的治疗策略，以抵消卵巢癌和骨肉瘤的CDDP耐药。CDDP诱导HIF-1α的稳定，导致其靶基因BNIP 3的表达。BNIP 3通过增加线粒体的分裂和降解速率来促进线粒体的自噬。这一过程最终提高了耐药癌细胞逃避CDDP细胞毒性的能力，通过消除其主要靶点之一，线粒体，细胞色素c从线粒体中释放出来引发细胞死亡。虽然BNIP 3表达可能是预测癌症患者化疗反应性的新预后因素，但靶向线粒体自噬可能是克服铂类耐药的新治疗方法。我们使用BioRender软件（BioRender.com）绘制示意图。
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. 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.
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影响因子：
3.4
作者：
Dorn GW 2nd
通讯作者：
Dorn GW 2nd
影响因子：
14.9
作者：
Colaprico A;Silva TC;Olsen C;Garofano L;Cava C;Garolini D;Sabedot TS;Malta TM;Pagnotta SM;Castiglioni I;Ceccarelli M;Bontempi G;Noushmehr H
通讯作者：
Noushmehr H
影响因子：
7.3
作者：
Bean GR;Ganesan YT;Dong Y;Takeda S;Liu H;Chan PM;Huang Y;Chodosh LA;Zambetti GP;Hsieh JJ;Cheng EH
通讯作者：
Cheng EH
影响因子：
4
作者：
Cseh, Anna Maria;Fabian, Zsolt;Sumegi, Balazs
通讯作者：
Sumegi, Balazs
影响因子：
21.3
作者：
Dowdle, William E.;Nyfeler, Beat;Murphy, Leon O.
通讯作者：
Murphy, Leon O.