Hydrogen peroxide-induced mitophagy contributes to laryngeal cancer cells survival via the upregulation of FUNDC1.
PURPOSE
The purpose of our study was to investigate an underlying mechanism that hydrogen peroxide-induced mitophagy contributed to laryngeal cancer cells survivals under oxidative stress condition.


METHODS
Tumor tissue and serum samples were collected from patients with laryngeal cancer. The Hep2 cell, a human laryngeal carcinoma cell, was used in in vitro experiments. The levels of lipid peroxidation were analyzed by ELISA. Knockdown of FUNDC1 was performed by RNAi. The changes of target proteins were determined by qRT-PCR and western blot. The cells were analyzed for changes in proliferation using cell counting kit-8 and mitophagy by the mitochondrial membrane potential assay and transmission electron microscopy.


RESULTS
FUNDC1 in laryngeal cancer tissues were relative to the levels of lipid peroxidation in laryngeal cancer patients, which suggested that FUNDC1 was associated with the status of oxidative stress in the laryngeal cancer patients. Hydrogen peroxide significantly induced the elevation of FUNDC1, a mitophagic factor, in a time- and dose-dependent manner in laryngeal cancer cells, which was dependent on ERK signal activation. Knockdown of FUNDC1 by the siRNA attenuated the survival of laryngeal cancer cells under hydrogen peroxide stimulation. Moreover, the elevated FUNDC1 was required for the occurrence of mitophagy under hydrogen peroxide stimulation, which was identified by transmission electron microscopy, the alterations of mitochondrial permeability transition and the specific mitochondrial protein, hsp60. Inhibition of mitophagy with cyclosporine A could also effectively attenuate the laryngeal cancer cells survival under hydrogen peroxide stimulation.


CONCLUSIONS
Hydrogen peroxide upregulated the expression of FUNDC1 through the activation of ERK1/2 signal to trigger a mitophagic response, giving laryngeal cancer cells a befit for survival. These findings suggested that FUNDC1 might be a potential target for the treatment of laryngeal cancer accompanied with high lipid peroxidation status.
['Hui|L|L|http://orcid.org/0000-0002-1444-1056', 'Wu|H|H|', 'Wang|T-W|TW|', 'Yang|N|N|', 'Guo|X|X|', 'Jang|X-J|XJ|']
D014408:Biomarkers, Tumor D016022:Case-Control Studies D002470:Cell Survival D005500:Follow-Up Studies D015972:Gene Expression Regulation, Neoplastic D006801:Humans D006861:Hydrogen Peroxide D007822:Laryngeal Neoplasms D015227:Lipid Peroxidation D008565:Membrane Proteins D008928:Mitochondria D024101:Mitochondrial Proteins D063306:Mitophagy D016877:Oxidants D010766:Phosphorylation D011379:Prognosis D014407:Tumor Cells, Cultured
Mitophagy Laryngeal cancer Cell survival FUNDC1 Hydrogen peroxide