Targeting FAM134B-mediated reticulophagy activates sorafenib-induced ferroptosis in hepatocellular carcinoma

  • Biochem Biophys Res Commun. 2022 Jan 22:589:247-253. doi: 10.1016/j.bbrc.2021.12.019.
Zhiqian Liu  1 ,  Changlin Ma  2 ,  Qi Wang  1 ,  Hao Yang  3 ,  Zhihua Lu  4 ,  Tao Bi  5 ,  Zongzhen Xu  3 ,  Tao Li  3 ,  Ling Zhang  6 ,  Yajie Zhang  6 ,  Jingfang Liu  7 ,  Xiaoqing Wei  8 ,  Jie Li  9
Affiliations
  • 1. Department of Hepatobiliary Surgery, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
  • 2. Department of Hepatobiliary Surgery, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China; Departments of Hepatobiliary Surgery, Jining No.1 People's Hospital, Jining, Shandong, 272001, China.
  • 3. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, 250014, China.
  • 4. Department of General Surgery, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong, 266035, China.
  • 5. Department of Gastrointestinal Surgery, Yantai Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong, 264003, China.
  • 6. Department of Reproduction Medicine, Jinan Maternal and Child Health Care Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250001, China.
  • 7. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, 250014, China. Electronic address: [email protected].
  • 8. Department of Reproduction Medicine, Jinan Maternal and Child Health Care Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250001, China. Electronic address: [email protected].
  • 9. Department of Hepatobiliary Surgery, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China. Electronic address: [email protected].
PMID: 34929448 DOI: 10.1016/j.bbrc.2021.12.019
Abstract

Ferroptosis is a kind of cell death closely related to selective Autophagy, such as ferritinophagy, lipophagy, clockophagy and chaperone-mediated Autophagy. However, the role of reticulophagy, which specifically degrades endoplasmic reticulum (ER) fragments (also known as ER-phagy), in Ferroptosis regulation is still unclear. In this study, we found that sorafenib (Ferroptosis inducer) can effectively activate the receptor protein FAM134B-mediated ER-phagy, and FAM134B knockdown not only blocked ER-phagy but also significantly strengthened cellular sensitivity to Ferroptosis without affecting macroautophagy. In vivo experiments also yielded similar results. These evidences provided new clues for Ferroptosis regulation. Subsequently, bioinformatic analysis combined with RNA binding protein immunoprecipitation and polyribosome fractionation preliminarily indicated that PABPC1 can interact with FAM134B mRNA and promote its translation. Taken together, this study revealed the role of the PABPC1-FAM134B-ER-phagy pathway on Ferroptosis, providing important evidence for novel anti-cancer strategies.

Keywords
FAM134B; Ferroptosis; PABPC1; Reticulophagy/ER-Phagy.
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