Melatonin inhibits lung cancer development by reversing the Warburg effect via stimulating the SIRT3/PDH axis

Xiangyun Chen, Bingjie Hao, Dan Li, Russel J. Reiter, Yidong Bai, Baigenzhin Abay, Guojie Chen, Shumeng Lin, Tiansheng Zheng, Yanbei Ren, Xiao Xu, Ming Li, Lihong Fan

Research output: Contribution to journalArticlepeer-review

Abstract

Recently, the morbidity and mortality from lung cancer have continued to increase. Mitochondrial dysfunction plays a key role in apoptosis, proliferation, and the bioenergetic reprogramming of cancer cells, especially for energy metabolism. Herein, we investigated the ability of melatonin (MLT) to influence lung cancer growth and explored the association between mitochondrial functions and the progression of lung tumors. The deacetylase, sirtuin 3 (Sirt3), is a pivotal player in maintenance of mitochondrial function, among participating in ATP production by regulating the acetylone and pyruvate dehydrogenase complex (PDH). We initially found that MLT inhibited lung cancer growth in the Lewis mouse model. Similarly, we observed that MLT inhibited the proliferation of lung cancer cells (A549, PC9, and LLC cells), and the underlying mechanism of MLT was related to reprogramming cancer cell metabolism, accompanied by a shift from cytosolic aerobic glycolysis to oxidative phosphorylation (OXPHOS). These changes were accompanied by higher ATP production, an elevated ATP production-coupled oxygen consumption rate (QCR), higher ROS levels, higher mito-ROS levels, and lower lactic acid secretion. Additionally, we observed that MLT improved mitochondrial membrane potential and the activities of complexes Ⅰ and Ⅳ in the electron transport chain. Importantly, we also found and verified that the foregoing changes resulted from activation of Sirt3 and PDH. As a result of these changes, MLT significantly enhanced mitochondrial energy metabolism to reverse the Warburg effect via increasing PDH activity with stimulation of Sirt3. Collectively, these findings suggest the potential use of melatonin as an anti-lung cancer therapy and provide a mechanistic basis for this proposal.

Original languageEnglish (US)
Article numbere12755
JournalJournal of pineal research
Volume71
Issue number2
DOIs
StatePublished - Sep 2021

Keywords

  • Lung cancer
  • Warburg effect
  • melatonin
  • mitochondria
  • oxidative phosphorylation
  • pyruvate dehydrogenase complex
  • sirtuin 3

ASJC Scopus subject areas

  • Endocrinology

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