Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Hypoxia-Induced ROS Promotes Mitochondrial Fission and Cisplatin Chemosensitivity via HIF-1α/Mff Regulation

Version 1 : Received: 4 November 2020 / Approved: 5 November 2020 / Online: 5 November 2020 (10:02:19 CET)

How to cite: Wu, K.; Mao, Y.; Chen, Q.; Zhang, B.; Zhang, S.; Wu, H.; Li, Y. Hypoxia-Induced ROS Promotes Mitochondrial Fission and Cisplatin Chemosensitivity via HIF-1α/Mff Regulation. Preprints 2020, 2020110204 (doi: 10.20944/preprints202011.0204.v1). Wu, K.; Mao, Y.; Chen, Q.; Zhang, B.; Zhang, S.; Wu, H.; Li, Y. Hypoxia-Induced ROS Promotes Mitochondrial Fission and Cisplatin Chemosensitivity via HIF-1α/Mff Regulation. Preprints 2020, 2020110204 (doi: 10.20944/preprints202011.0204.v1).

Abstract

Chemotherapy treatment based on Cisplatin (CDDP) is established as the drug of choice for head and neck squamous cell carcinoma (HNSCC). Malignant tumors respond to microenvironment alteration through a dynamic balance of mitochondrial fission and fusion. HNSCC is known to have hypoxic conditions, yet the effects and underlying mechanisms of hypoxia on chemosensitivity and mitochondrial dynamics remain unclear. We found that hypoxia promoted mitochondrial fission and CDDP sensitivity in HNSCC cells. Importantly, Mff was shown to be correlated with chemosensitivity in clinical samples of HNSCC that underwent a hypoxic condition. Hypoxia-inducible factor 1 α-subunit (HIF-1α) dramatically increased Mff transcriptional expression and directly bound to Mff. Hypoxia enhanced the release of reactive oxygen species (ROS) and upregulated the expression of Mff via HIF-1α in HNSCC cells. ROS depletion in HNSCC cells attenuated HIF-1α, Mff expression, and mitochondrial fission. Moreover, a knockdown of Mff suppressed hypoxia-induced mitochondrial fission and decreased CDDP chemosensitivity in vivo and in vitro. Our findings revealed that the hypoxia-induced release of ROS promoted mitochondrial fission and CDDP chemosensitivity via the regulation of HIF-1α/Mff in HNSCC cells, indicating that Mff may serve as a new biomarker to predict neoadjuvant chemosensitivity in HNSCC patients

Subject Areas

hypoxia; cisplatin sensitivity; mitochondrial fission; ROS; head and neck squamous cell carcinoma

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