Hypoxia-induced ROS promotes mitochondrial fission and cisplatin chemosensitivity via HIF-1α/Mff regulation in head and neck squamous cell carcinoma

Cell Oncol (Dordr). 2021 Oct;44(5):1167-1181. doi: 10.1007/s13402-021-00629-6. Epub 2021 Aug 30.

Abstract

Purpose: Chemotherapy based on cisplatin (CDDP) has been established as the treatment of choice for head and neck squamous cell carcinoma (HNSCC). Malignant tumors respond to microenvironmental alterations through a dynamic balance between mitochondrial fission and fusion. HNSCCs are known to exhibit hypoxic conditions, yet the respective effects and underlying mechanisms of hypoxia on chemosensitivity and mitochondrial dynamics remain to be resolved.

Methods: The effect of hypoxia on the chemosensitivity of HNCC cells was determined by flow cytometry. Mitochondrial fission factor (Mff) expression was assessed by RT-PCR and Western blotting in hypoxic HNSCC cells, and further verified in primary CDDP-sensitive and CDDP-resistant HSNCC samples. The biological function of Mff was evaluated by loss of function and gain of function analyses, both in vitro and in vivo.

Results: We found that hypoxia promoted mitochondrial fission and CDDP sensitivity in HNSCC cells. Importantly, Mff was found to be correlated with chemosensitivity in primary clinical samples under hypoxic conditions. Hypoxia-inducible factor 1α (HIF-1α) was found to markedly increase Mff transcription and to directly bind 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 expression, Mff expression and mitochondrial fission. Moreover, Mff knockdown led to suppression of hypoxia-induced mitochondrial fission and to decreased CDDP chemosensitivity in vivo and in vitro.

Conclusions: Our findings indicate that hypoxia-induced release of ROS can promote mitochondrial fission and CDDP chemosensitivity via HIF1α/Mff regulation in HNSCC cells, indicating that Mff may serve as a biomarker to predict neoadjuvant chemosensitivity in HNSCC patients and as a target for overcoming chemoresistance.

Keywords: Cisplatin sensitivity; Head and neck squamous cell carcinoma; Hypoxia; Mitochondrial fission; ROS.

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cisplatin / therapeutic use*
  • Gene Expression Regulation, Neoplastic / drug effects
  • HEK293 Cells
  • Head and Neck Neoplasms / drug therapy
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / metabolism*
  • Humans
  • Hypoxia / genetics
  • Hypoxia / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mitochondrial Dynamics / drug effects*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • RNA Interference
  • Reactive Oxygen Species / metabolism*
  • Tumor Hypoxia / genetics
  • Xenograft Model Antitumor Assays / methods

Substances

  • Antineoplastic Agents
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Membrane Proteins
  • Mff protein, human
  • Mitochondrial Proteins
  • Reactive Oxygen Species
  • Cisplatin