2. Academic Validation
  3. Simultaneous treatment with sorafenib and glucose restriction inhibits hepatocellular carcinoma in vitro and in vivo by impairing SIAH1-mediated mitophagy

Simultaneous treatment with sorafenib and glucose restriction inhibits hepatocellular carcinoma in vitro and in vivo by impairing SIAH1-mediated mitophagy

  • Exp Mol Med. 2022 Nov 16. doi: 10.1038/s12276-022-00878-x.
Jing Zhou # 1 2,  Ji Feng # 3,  Yong Wu # 3,  Hui-Qi Dai # 2 3,  Guang-Zhi Zhu # 4,  Pan-Hong Chen 1,  Li-Ming Wang 2,  Guang Lu 2,  Xi-Wen Liao 4,  Pei-Zhi Lu 3,  Wen-Jing Su 3,  Shing Chuan Hooi 2,  Xin-Pin Ye 4,  Han-Ming Shen 5 6,  Tao Peng 7 8,  Guo-Dong Lu 9 10
Affiliations

Affiliations

  • 1 Department of Physiology, School of Basic Medical Sciences, Guangxi Medical University, 530021, Nanning, Guangxi Province, P. R. China.
  • 2 Department of Physiology, National University of Singapore, Singapore, 117593, Singapore.
  • 3 Department of Toxicology, School of Public Health, Guangxi Medical University, 530021, Nanning, Guangxi Province, P. R. China.
  • 4 Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, 530021, Nanning, Guangxi Province, P. R. China.
  • 5 Department of Physiology, National University of Singapore, Singapore, 117593, Singapore. hmshen@um.edu.mo.
  • 6 Faculty of Health Sciences, University of Macau, Macau, P. R. China. hmshen@um.edu.mo.
  • 7 Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, 530021, Nanning, Guangxi Province, P. R. China. p98720p@163.com.
  • 8 Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education; Guangxi Key laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), 530021, Nanning, Guangxi Province, P. R. China. p98720p@163.com.
  • 9 Department of Toxicology, School of Public Health, Guangxi Medical University, 530021, Nanning, Guangxi Province, P. R. China. golden_lu@hotmail.com.
  • 10 Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education; Guangxi Key laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), 530021, Nanning, Guangxi Province, P. R. China. golden_lu@hotmail.com.
  • # Contributed equally.
PMID: 36385558 DOI: 10.1038/s12276-022-00878-x
Abstract

Transarterial chemoembolization (TACE) is the first-line treatment for unresectable intermediate-stage hepatocellular carcinoma (HCC). It is of high clinical significance to explore the synergistic effect of TACE with antiangiogenic inhibitors and the molecular mechanisms involved. This study determined that glucose, but not other analyzed nutrients, offered significant protection against cell death induced by sorafenib, as indicated by glucose deprivation sensitizing cells to sorafenib-induced cell death. Next, this synergistic effect was found to be specific to sorafenib, not to lenvatinib or the chemotherapeutic drugs cisplatin and doxorubicin. Mechanistically, sorafenib-induced Mitophagy, as indicated by PINK1 accumulation, increased the phospho-poly-ubiquitination modification, accelerated mitochondrial membrane protein and mitochondrial DNA degradation, and increased the amount of mitochondrion-localized mKeima-Red engulfed by lysosomes. Among several E3 ubiquitin ligases tested, SIAH1 was found to be essential for inducing mitophagy; that is, SIAH1 silencing markedly repressed Mitophagy and sensitized cells to sorafenib-induced death. Notably, the combined treatment of glucose restriction and sorafenib abolished ATP generation and Mitophagy, which led to a high cell death rate. Oligomycin and antimycin, inhibitors of electron transport chain complexes, mimicked the synergistic effect of sorafenib with glucose restriction to promote cell death mediated via Mitophagy inhibition. Finally, inhibition of the glucose transporter by canagliflozin (a clinically available drug used for type-II diabetes) effectively synergized with sorafenib to induce HCC cell death in vitro and to inhibit xenograft tumor growth in vivo. This study demonstrates that simultaneous treatment with sorafenib and glucose restriction is an effective approach to treat HCC, suggesting a promising combination strategy such as transarterial sorafenib-embolization (TASE) for the treatment of unresectable HCC.

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