Reduction in mitochondrial oxidative stress mediates hypoxia-induced resistance to cisplatin in human transitional cell carcinoma cells

• Published in: Neoplasia (New York, N.Y.) Vol. 23; no. 7; pp. 653 - 662
• Main Authors: Kim, Myung-Chul, Hwang, Sung-Hyun, Yang, Yeseul, Kim, Na-Yon, Kim, Yongbaek
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2021; Neoplasia Press; Elsevier
• Subjects: Apoptosis - drug effects; Carcinoma, Transitional Cell - drug therapy; Carcinoma, Transitional Cell - metabolism; Cell Line, Tumor; Cell Survival - drug effects; Cisplatin - pharmacology; DNA Fragmentation - drug effects; Drug resistance; Drug Resistance, Neoplasm - drug effects; Humans; Hypoxia; Hypoxia - metabolism; Membrane Potential, Mitochondrial - drug effects; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - ultrastructure; Models, Biological; mtDNA; Original Research; Oxidative stress; Oxidative Stress - drug effects; Reactive Oxygen Species - metabolism; Tumor Hypoxia - drug effects; Tumor Hypoxia - genetics; Oxidative stress; mtDNA; HIF-1α; Drug resistance; H2O2; MTT; MMP; NAC; Mitochondria; CCCP; n.s; TCC; ROS; Hypoxia; EtBr; JC-1
• ISSN: 1476-5586; 1522-8002; 1476-5586
• DOI: 10.1016/j.neo.2021.05.013

Tumor hypoxia is known to promote the acquisition of more aggressive phenotypes in human transitional cell carcinoma (TCC), including drug resistance. Accumulating evidence suggests that mitochondria play a central role in the chemoresistance of TCC. However, the role of mitochondria in the hypoxia-induced drug resistance in TCC remains elusive. The present study investigated the function of mitochondria in the drug resistance using a TCC cell line under hypoxic conditions. In vitro hypoxia (0.1% O2, 48 h) was achieved by incubating TCC cells in air chamber. Mitochondrial events involving hypoxia-induced drug resistance were assessed. Hypoxia significantly reduced the cisplatin-induced apoptosis of TCC cells. Additionally, hypoxia substantially decreased the level of mitochondrial reactive oxygen species (ROS) generated by cisplatin treatment. Analogously, elimination of mitochondrial ROS significantly rescued cells from cisplatin-induced apoptosis. Hypoxia enhanced mitochondrial hyperpolarization, which was not related to ATP production or the reversal of ATP synthase activity. The mitochondrial DNA (mtDNA) amplification efficiency data illustrated that hypoxia significantly prevented oxidative damage to the mitogenome. Moreover, transmission electron microscopy revealed that cisplatin-induced disruption of the mitochondrial ultrastructure was abated under hypoxic conditions. Notably, depletion of mtDNA by ethidium bromide abrogated hypoxia-induced resistance to cisplatin. Taken together, the present study demonstrated that TCC cells exposed to hypoxic conditions rendered mitochondria less sensitive to oxidative stress induced by cisplatin treatment, leading to enhanced drug resistance.