Up-regulation of GSTT1 in serous ovarian cancer associated with resistance to TAXOL / carboplatin

Jing Zhang,Lin Guo,Suhong Xie,Yanchun Wang,Hui Zheng,Minjie Deng,Lei Zhou,Xiaolin Guan,Xiaoyu Tang,Renquan Lu

doi:10.1186/s13048-021-00873-2

Abstract

Serous ovarian cancer (SOC) is the most common women cancer and the leading cause of cancer-related mortality among the gynaecological malignancies. Although effective chemotherapeutics combined with surgery are developed for the treatment, the five-year survival rate is unsatisfactory due to chemoresistance. To overcome this shortcoming of chemotherapy, we established taxol and carboplatin resistant SOC cell lines for the understandings of the molecular and cellular mechanisms of chemoresistance. Here, we found that these chemoresistant cell lines showed less viability and proliferation, due to more cells arrested at G0/G1 phase. Glutathione-S-transferases-theta1 (GSTT1) was significantly upregulated in these chemoresistant cells, along with other chemoresistant genes. Meanwhile, GSTT1 expression was also significantly upregulated in the SOC patient tissues after taxol treatment, indicating this upregulation was physiologically relevant to chemotherapy. Further, suppression of GSTT1 expression by shRNA in SOC cell lines led to more sensitivity to drug treatment, through increasing divided cells and promoting cell death. Moreover, the expression of DNA topoisomerase 1 (Topo I) was in synergy with that of GSTT1 in the chemoresistant cells, and GSTT1 can bind to Topo I in vitro, which suggested GSTT1 could function through DNA repair mechanism during chemoresistance. In summary, our data imply that GSTT1 may be a potential biomarker or indicator of drug resistance in serous ovarian cancer.

Highlights

Ovarian cancer (OC) is the most lethal gynaecologic cancer, which accounts for 4% of all kinds of women’s cancer
We show here that GlutathioneS-transferases-T1 (GSTT1), a member of metabolic enzymes that catalyse the conjugation of glutathione onto endogenous and xenobiotic reactive intermediates [7, 8], and a previously showed cancer related gene, is related to the chemoresistance of serous ovarian cancer (SOC) cell lines
Establishment of taxol / carboplatin‐resistant (TAX/CBP) SOC cell lines To explore the mechanism of combined resistance of taxol and carboplatin in SOC cell lines, taxol / carboplatin-resistant serous ovarian cancer (SOC) cells, SKOV3TAX/CBP and HO8910-TAX/CBP were screened in the presence of long-term drug treatment, two different parental cell lines, SKOV3 and HO8910 being used in the experiments

Summary

Introduction

Ovarian cancer (OC) is the most lethal gynaecologic cancer, which accounts for 4% of all kinds of women’s cancer. Chemotherapy is one of effective treatments for ovarian cancer. Many chemotherapeutics, such as taxol (TAX), carboplatin (CBP), doxorubicin, cyclophosphamide, etc., are Despite advances in chemotherapy, the overall five-year survival rate for SOC is just roughly 20%, mainly due to chemoresistance, which leads to cancer recurrence and treatment failure for SOC patients [3, 4]. [5, 6] Molecules involved in those processes may play roles in regulating chemoresistance, and could provide potential targets for drug treatment or diagnosis, in order to improve survival rates for ovarian cancer patients

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Conclusion