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bioRxiv · 10.1101/2023.07.12.548688

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

Wang, S.·Cheng, H.·Li, M.·Wu, H.·Zhang, S.·Gao, D.·Huang, Y.·Guo, K.
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Abstract

Although increasing studies has demonstrated that cell competition widely involved in the growth and homeostasis of multicellular organisms is closely linked to tumorigenesis and development, the mechanistic contributions to the association between tumor cell competition-driven heterogeneity and drug resistance remains ill-defined. In our study, lenvitinib-resistant hepatocellular carcinoma (HCC) cells display obviously competitive growth dominance against sensitive cells through reprogramming energy metabolism. Mechanistically, when BCL2 interacting protein3 (BNIP3) overexpression activates mitophagy activity in lenvatinib-resistant HCC cells, energy imbalance signal caused by reduced mitochondrial oxidative phosphorylation levels provokes the phosphorylation of AMP-activated protein kinase (AMPK) sensor; subsequently, enabled AMPK specifically targets enolase 2 (ENO2) to enhance glycolysis and eventually promots the competitive capacity and dominant growth. Of note, BNIP3 deficiency shows certain inhibition of cell competition outcome. 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; meanwhile this work recognaizes BNIP3 as a promising target to overcome HCC drug resistance.

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Wang, S., Cheng, H., Li, M., Wu, H., Zhang, S., Gao, D., Huang, Y., Guo, K.. 2023-07-12. BNIP3-mediated mitophagy boosts the competitive dominant growth of lenvatinib resistant cells via reprogramming energy metabolism in HCC. https://doi.org/10.1101/2023.07.12.548688

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