Translocation of IGF-1R in endoplasmic reticulum enhances SERCA2 activity to trigger Ca2+ER perturbation in hepatocellular carcinoma

Yanan Li; Keqin Li; Ting Pan; Qiaobo Xie; Yuyao Cheng; Xinfeng Wu; Rui Xu; Xiaohui Liu; Li Liu; Jiangming Gao; Wenmin Yuan; Xianjun Qu; Shuxiang Cui

doi:10.1016/j.apsb.2023.05.031

Translocation of IGF-1R in endoplasmic reticulum enhances SERCA2 activity to trigger Ca²⁺_ER perturbation in hepatocellular carcinoma

Acta Pharm Sin B. 2023 Sep;13(9):3744-3755. doi: 10.1016/j.apsb.2023.05.031. Epub 2023 May 27.

Authors

Yanan Li¹, Keqin Li², Ting Pan¹, Qiaobo Xie², Yuyao Cheng¹, Xinfeng Wu², Rui Xu², Xiaohui Liu², Li Liu³, Jiangming Gao³, Wenmin Yuan³, Xianjun Qu², Shuxiang Cui¹

Affiliations

¹ Department of Toxicology and Sanitary Chemistry, Beijing Key Laboratory of Environmental Toxicology, School of Public Health, Capital Medical University, Beijing 100069, China.
² Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.
³ Department of Pharmacology, Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China.

Abstract

The well-known insulin-like growth factor 1 (IGF1)/IGF-1 receptor (IGF-1R) signaling pathway is overexpressed in many tumors, and is thus an attractive target for cancer treatment. However, results have often been disappointing due to crosstalk with other signals. Here, we report that IGF-1R signaling stimulates the growth of hepatocellular carcinoma (HCC) cells through the translocation of IGF-1R into the ER to enhance sarco-endoplasmic reticulum calcium ATPase 2 (SERCA2) activity. In response to ligand binding, IGF-1Rβ is translocated into the ER by β-arrestin2 (β-arr2). Mass spectrometry analysis identified SERCA2 as a target of ER IGF-1Rβ. SERCA2 activity is heavily dependent on the increase in ER IGF-1Rβ levels. ER IGF-1Rβ phosphorylates SERCA2 on Tyr⁹⁹⁰ to enhance its activity. Mutation of SERCA2-Tyr⁹⁹⁰ disrupted the interaction of ER IGF-1Rβ with SERCA2, and therefore ER IGF-1Rβ failed to promote SERCA2 activity. The enhancement of SERCA2 activity triggered Ca²⁺_ER perturbation, leading to an increase in autophagy. Thapsigargin blocked the interaction between SERCA2 and ER IGF-1Rβ and therefore SERCA2 activity, resulting in inhibition of HCC growth. In conclusion, the translocation of IGF-1R into the ER triggers Ca²⁺_ER perturbation by enhancing SERCA2 activity through phosphorylating Tyr⁹⁹⁰ in HCC.

Keywords: Ca2+ER perturbation; Endoplasmic reticulum (ER); HCC; IGF-1R; SERCA2; SERCA2Y990; Thapsigargin; βarrestin-2 (β-arr2).