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©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
γ-aminobutyric acid B2 receptor: A potential therapeutic target for cholangiocarcinoma in patients with diabetes mellitus
Charupong Saengboonmee, Supannika Sorin, Sakkarn Sangkhamanon, Surang Chomphoo, Somsiri Indramanee, Wunchana Seubwai, Kanyarat Thithuan, Ching-Feng Chiu, Seiji Okada, Marie-Claude Gingras, Sopit Wongkham
Charupong Saengboonmee, Supannika Sorin, Somsiri Indramanee, Kanyarat Thithuan, Sopit Wongkham, Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
Charupong Saengboonmee, Supannika Sorin, Sakkarn Sangkhamanon, Somsiri Indramanee, Wunchana Seubwai, Sopit Wongkham, Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
Charupong Saengboonmee, Supannika Sorin, Sakkarn Sangkhamanon, Somsiri Indramanee, Wunchana Seubwai, Sopit Wongkham, Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
Sakkarn Sangkhamanon, Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
Surang Chomphoo, Department of Anatomy, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
Wunchana Seubwai, Department of Forensic Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
Ching-Feng Chiu, Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei 11031, Taiwan
Seiji Okada, Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto 860-0811, Japan
Marie-Claude Gingras, Human Genome Sequencing Center, Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX 77030, United States
Marie-Claude Gingras, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, United States
Author contributions: Saengboonmee C, Seubwai W, Gingras MC, and Wongkham S conceptualized the research; Saengboonmee C, Sorin S, Sangkhamanon S, Indramanee S, Chomphoo S, and Thithuan K designed and performed the experiments; Saengboonmee C, Sorin S, Sangkhamanon S, Chomphoo S, Seubwai W, Chiu CF, Okada S, Gingras MC, and Wongkham S analyzed the data; Okada S and Gingras MC contributed research resources and analysis tools; Saengbonmee C and Sorin S wrote the manuscript draft; Saengboonmee C, Chiu CF, Okada S, Gingras MC, and Wongkham S reviewed and edited the manuscript; and all authors read and approved the final version of the manuscript.
Supported by the Research Grant for Young Talented Scholars, National Research Council of Thailand, No. N41A640108.
Institutional review board statement: The protocol of this study has been reviewed and approved by the Khon Kaen University Ethics Committee for Human Research (approval No. HE641441), based on the Declaration of Helsinki and the ICH-Good Clinical Practice Guidelines.
Informed consent statement: Written informed consent was obtained from all participants.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Charupong Saengboonmee, MD, PhD, Doctor, Lecturer, Department of Biochemistry, Faculty of Medicine, Khon Kaen University, 123 Mitraphap Highway, Khon Kaen 40002, Thailand. charusa@kku.ac.th
Received: February 23, 2023
Peer-review started: February 23, 2023
First decision: May 16, 2023
Revised: June 5, 2023
Accepted: July 5, 2023
Article in press: July 5, 2023
Published online: July 28, 2023
ARTICLE HIGHLIGHTS
Research background
The association between diabetes mellitus (DM) and cholangiocarcinoma (CCA) progression has been established with unclear mechanisms. Our previous study showed that γ-aminobutyric acid B2 receptor (GABBR2) is among the top 5 upregulated genes in CCA cells cultured in high glucose (HG). Thus, GABBR2 is highly potential for a repurposing aim in CCA treatment.
Research motivation
Approximately 60% of Thai patients with CCA had fasting blood glucose in a range of pre-diabetes or DM. Targeting the molecules underlying hyperglycemia-induced aggressiveness of CCA cells might improve the prognosis of CCA patients with DM.
Research objectives
This study aimed to investigate the effects of hyperglycemia on GABBR2 expression and the potential use of GABBR2 as a CCA therapeutic target.
Research methods
CCA cells cultured in normal glucose or HG conditions were used as models of in vitro euglycemia and hyperglycemia, respectively. Baclofen, a GABBR2 agonist, was used to study the functional roles of CCA cells. Western blot, immunocytofluorescence, and immunohistochemistry were used to study molecular mechanisms.
Research results
HG induced GABBR2 expression in both cell lines and in patients’ CCA tissues. Baclofen treatment significantly suppressed CCA cell growth, while cells cultured in HG showed a significantly higher sensitivity. The effects of baclofen on CCA cell growth were achieved by the suppression of the signal transducer and activator of transcription 3 and glycogen synthase kinase 3/β-catenin pathways.
Research conclusions
The expression of GABBR2 in CCA is induced in hyperglycemic conditions. Baclofen significantly suppresses the growth of CCA cells and thus holds a high promise as a repurposing drug for CCA treatment.
Research perspectives
Investigating baclofen’s effects at an optimal therapeutic dosage in in vivo models would verify the present work and facilitate the translation for clinical study in CCA cases.
