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

doi:10.3390/biomedicines10061350

Isoliquiritigenin Inhibits Gastric Cancer Stemness, Modulates Tumor Microenvironment, and Suppresses Tumor Growth through Glucose-Regulated Protein 78 Downregulation

Biomedicines. 2022 Jun 8;10(6):1350. doi: 10.3390/biomedicines10061350.

Authors

Chien-Hsing Lee^{1

2

3

4}, Hsin-Yi Tsai^{5

6}, Chun-Lin Chen⁷, Jen-Lung Chen⁸, Chao-Chun Lu⁵, Yi-Ping Fang⁵, Deng-Chyang Wu^{9

10

11}, Yaw-Bin Huang^{2

5}, Ming-Wei Lin^{6

11

12}

Affiliations

¹ Department of Pharmacology, School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
² Drug Development and Value Creation Research Center, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan.
³ Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan.
⁴ Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan.
⁵ School of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
⁶ Department of Medical Research, E-Da Hospital/E-Da Cancer Hospital, Kaohsiung 82445, Taiwan.
⁷ Department of Biological Science, National Sun Yat-sen University, Kaohsiung 80424, Taiwan.
⁸ Division of General Surgery, Department of Surgery, E-Da Hospital, Kaohsiung 82445, Taiwan.
⁹ Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan.
¹⁰ Department of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
¹¹ Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
¹² Department of Nursing, College of Medicine, I-Shou University, Kaohsiung 82445, Taiwan.

Abstract

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.

Keywords: GRP78; cancer stemness; chemosensitivity; gastric cancer; isoliquiritigenin; tumor microenvironment.

Abstract

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