Isoliquiritigenin Inhibits Gastric Cancer Stemness, Modulates Tumor Microenvironment, and Suppresses Tumor Growth through Glucose-Regulated Protein 78 Downregulation
Chien-Hsing Lee,
Hsin-Yi Tsai,
Chun-Lin Chen,
Jen-Lung Chen,
Chao-Chun Lu,
Yi-Ping Fang,
Deng-Chyang Wu,
Yaw-Bin Huang,
Ming-Wei Lin
Affiliations
Chien-Hsing Lee
Department of Pharmacology, School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
Hsin-Yi Tsai
School of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
Chun-Lin Chen
Department of Biological Science, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
Jen-Lung Chen
Division of General Surgery, Department of Surgery, E-Da Hospital, Kaohsiung 82445, Taiwan
Chao-Chun Lu
School of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
Yi-Ping Fang
School of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
Deng-Chyang Wu
Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
Yaw-Bin Huang
Drug Development and Value Creation Research Center, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
Ming-Wei Lin
Department of Medical Research, E-Da Hospital/E-Da Cancer Hospital, Kaohsiung 82445, Taiwan
Chemotherapy is the treatment of choice for gastric cancer; however, the currently available therapeutic drugs for treatment have limited efficacy. Cancer stemness and the tumor microenvironment may play crucial roles in tumor growth and chemoresistance. Glucose-regulated protein 78 (GRP78) is an endoplasmic reticulum chaperone facilitating protein folding and cell homeostasis during stress and may participate in chemoresistance. Isoliquiritigenin (ISL) is a bioactive flavonoid found in licorice. In this study, we demonstrated the role of GRP78 in gastric cancer stemness and evaluated GRP78-mediated stemness inhibition, tumor microenvironment regulation, and chemosensitivity promotion by ISL. ISL not only suppressed GRP78-mediated gastric cancer stem cell–like characteristics, stemness-related protein expression, and cancer-associated fibroblast activation but also gastric tumor growth in xenograft animal studies. The findings indicated that ISL is a promising candidate for clinical use in combination chemotherapy.
