Research Paper Volume 14, Issue 12 pp 5097—5115
Calreticulin nuclear translocalization alleviates CaM/CaMKII/CREB signaling pathway to enhance chemosensitivity in HDAC inhibitor-resistant hepatocellular carcinoma cells
- 1 Division of Hematology and Oncology, Department of Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung 802, Taiwan
- 2 School of Medicine, National Defense Medical Center, Taipei 114, Taiwan
- 3 Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan
- 4 Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung 406, Taiwan
- 5 Ph.D. Program for Biotechnology Industry, China Medical University, Taichung 406, Taiwan
- 6 Department of Surgery, Division of Colorectal Surgery, Taichung Veterans General Hospital, Taichung 407, Taiwan
- 7 Faculty of Medicine, National Yang-Ming University, Taipei 112, Taiwan
- 8 Department of Hematology and Oncology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, School of Medicine Tzu Chi University, Hualien 97004, Taiwan
- 9 School of Life Science, National Taiwan Normal University, Taipei 116, Taiwan
- 10 School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- 11 Department of Surgical Pathology, Changhua Christian Hospital, Changhua 500, Taiwan
- 12 Center of Stem Cell and Precision Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan
- 13 Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, Taiwan
- 14 Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan
- 15 Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan
- 16 Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung 413, Taiwan
- 17 Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien 970, Taiwan
Received: October 30, 2021 Accepted: May 23, 2022 Published: June 20, 2022
https://doi.org/10.18632/aging.204131How to Cite
Copyright: © 2022 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Calreticulin (CRT) is located in the endoplasmic reticulum (ER), it helps proteins fold correctly inside the ER, and acts as a modulator of Ca2+ homeostasis. Aberrant expression of CRT is implicated in several cancer types, qualifying CRT as a potential therapeutic target. However, it remains unclear how CRT affects specific oncogenic pathways. In this study, we used histone deacetylase inhibitors (HDACis) to establish drug-resistant liver cancer cells and further analyzed the molecular mechanism of development of drug resistance in those cells. The 2D gel electrophoresis and RT-PCR data showed that CRT was downregulated in HDACis-resistant cells by comparing with HA22T parental cells. We previously elucidated the development of drug-resistance in HCC cells via activation of PP1-eIF2α pathway, but not via ER stress pathway. Here, we show that thapsigargin induced ER stress through mechanism other than ER stress downstream protein GRP78-PERK to regulate CRT expression in HDACis-R cells. Moreover, the expression level of CRT was not the main cause of apoptosis in HDACis-resistant cells. Mechanistic studies identified the apoptosis factors in the nucleus—the HDACis-mediated overexpression of CRT, CRT translocation to the cell nucleus, and reduced CaM/CaMKII/CREB pathway—that led to chemosensitivity in HDACis-R HCC cells.