2. Academic Validation
  3. Artesunate Sensitizes Human hepatocellular carcinoma to sorafenib via exacerbating AFAP1L2-SRC-FUNDC1 axis-dependent mitophagy

Artesunate Sensitizes Human hepatocellular carcinoma to sorafenib via exacerbating AFAP1L2-SRC-FUNDC1 axis-dependent mitophagy

  • Autophagy. 2023 Sep 21. doi: 10.1080/15548627.2023.2261758.
Zhaochen Ma 1,  Wenjia Chen 1,  Yudong Liu 1,  Lingxiang Yu 2,  Xia Mao 1,  Xiaodong Guo 2,  Funeng Jiang 3,  Qiuyan Guo 4,  Na Lin 1,  Yanqiong Zhang 1
Affiliations

Affiliations

  • 1 Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.
  • 2 The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China.
  • 3 Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, South China University of Technology, Guangzhou, China.
  • 4 Artemisinin Research Center, China Academy of Chinese Medical Sciences, Beijing, China.
PMID: 37733919 DOI: 10.1080/15548627.2023.2261758
Abstract

Sorafenib is the most widely used first-line drug for the treatment of the advanced hepatocellular carcinoma (HCC). Unfortunately, sorafenib resistance often limits its therapeutic efficacy. To evaluate the efficacy of artesunate against sorafenib-resistant HCC and to investigate its underlying pharmacological mechanisms, a "sorafenib resistance related gene-ART candidate target" interaction network was constructed, and a signaling axis consisting with artesunate candidate target AFAP1L2 and sorafenib target Src, and the downstream FUNDC1-dependent Mitophagy was identified as a major contributor to the sorafenib resistance and a potential way of artesunate to mitigate resistance. Notably, our clinical data demonstrated that AFAP1L2 expression in HCC tissues was markedly higher than that in adjacent non-cancerous liver tissues (P < 0.05), and high AFAP1L2 expression was also significantly associated with an unfavorable overall survival of HCC patients (P < 0.05). Experimentally, AFAP1L2 was overexpressed in sorafenib resistant cells, leading to the activation of downstream SRC-FUNDC1 signaling axis, further blocking the FUNDC1 recruitment of LC3B to mitochondria and inhibiting the activation of Mitophagy, based on both in vitro and in vivo systems. Moreover, artesunate significantly enhanced the inhibitory effects of sorafenib on resistant cells and tumors by inducing excessive Mitophagy. Mechanically, artesunate reduced the expression of AFAP1L2 protein, suppressed the phosphorylation levels of Src and FUNDC1 proteins, promoted the FUNDC1 recruitment of massive LC3B to mitochondria, and further overactivated the Mitophagy and subsequent cell Apoptosis of sorafenib resistant cells. In conclusion, artesunate may be a promising strategy to mitigate sorafenib resistance in HCC via exacerbating AFAP1L2-SRC-FUNDC1 axis-dependent Mitophagy.

Keywords

AFAP1L2; artesunate; hepatocellular carcinoma; mitophagy; sorafenib resistance.

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