BNIP3-mediated mitophagy boosts the competitive growth of Lenvatinib-resistant cells via energy metabolism reprogramming in HCC

  • Cell Death Dis. 2024 Jul 5;15(7):484. doi: 10.1038/s41419-024-06870-9.
Sikai Wang  #  1 ,  Hongxia Cheng  #  2 ,  Miaomiao Li  #  3 ,  Dongmei Gao  #  1 ,  Haoran Wu  4 ,  Shanshan Zhang  4 ,  Yilan Huang  1 ,  Kun Guo  5  6
Affiliations
  • 1. Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, 200032, China.
  • 2. Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200032, China.
  • 3. Endoscopy Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
  • 4. Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
  • 5. Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, 200032, China. [email protected].
  • 6. Cancer Research Center, Institute of Biomedical Science, Fudan University, Shanghai, 200032, China. [email protected].
  • # Contributed equally.
PMID: 38969639 DOI: 10.1038/s41419-024-06870-9
Abstract

An increasing evidence supports that cell competition, a vital selection and quality control mechanism in multicellular organisms, is involved in tumorigenesis and development; however, the mechanistic contributions to the association between cell competition and tumor drug resistance remain ill-defined. In our study, based on a contructed lenvitinib-resistant hepatocellular carcinoma (HCC) cells display obvious competitive growth dominance over sensitive cells through reprogramming energy metabolism. Mechanistically, the hyperactivation of BCL2 interacting protein3 (BNIP3) -mediated Mitophagy in lenvatinib-resistant HCC cells promotes glycolytic flux via shifting energy production from mitochondrial Oxidative Phosphorylation to glycolysis, by regulating AMP-activated protein kinase (AMPK) -enolase 2 (ENO2) signaling, which perpetually maintaining lenvatinib-resistant HCC cells' competitive advantage over sensitive HCC cells. Of note, BNIP3 inhibition significantly sensitized the anti-tumor efficacy of lenvatinib in HCC. Our findings emphasize a vital role for BNIP3-AMPK-ENO2 signaling in maintaining the competitive outcome of lenvitinib-resistant HCC cells via regulating energy metabolism reprogramming; meanwhile, this work recognizes BNIP3 as a promising target to overcome HCC drug resistance.

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