Research Paper Volume 12, Issue 13 pp 13220—13233
Cancer-associated fibroblasts-derived gamma-glutamyltransferase 5 promotes tumor growth and drug resistance in lung adenocarcinoma
- 1 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, P. R. China
- 2 State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, P. R. China
- 3 Department of Clinical Oncology Center, The University of Hongkong-Shenzhen Hospital, Shenzhen, P. R. China
- 4 Department of Clinical Oncology, The University of Hong Kong, Hong Kong, P. R. China
Received: December 17, 2019 Accepted: May 25, 2020 Published: July 8, 2020
https://doi.org/10.18632/aging.103429How to Cite
Copyright © 2020 Wei 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
Gamma-glutamyltransferase 5 (GGT5) is a member of the gamma-glutamyl transpeptidase gene family with the capacity of cleaving the gamma-glutamyl moiety of glutathione, but its role in cancer progression has never been revealed. In this study, we found that gene GGT5 was highly expressed in cancer-associated fibroblasts (CAFs) in lung adenocarcinoma, predicting the unfavorable survival of patients with lung adenocarcinoma. Cell growth, foci formation and spheres formation analyses showed that cancer cell proliferation was attenuated under treatment with the conditioned media from GGT5-silenced CAFs. Moreover, high expression of GGT5 in CAFs enhanced the drug resistance of cancer cells by increasing intracellular glutathione and reducing the intracellular reactive oxygen species in cancer cells. In mouse xenograft model, we proved that targeting GGT5 with a small-molecule inhibitor GGsTop could inhibit tumor growth and increase the chemosensitivity of cancer cells. Taken together, our study illuminates that high level of GGT5 in CAFs contributes to cancer cell survival and drug resistance, indicating that GGT5 may be a promising therapeutic target in lung adenocarcinoma.