GATA1 Promotes Gemcitabine Resistance in Pancreatic Cancer through Antiapoptotic Pathway.

Zhenyu Chang,Xinjin Gu,Zelong Yang,Chengjian Guan,Qinong Ye,Jie Liu,Yanan Zhang,Rong Liu,Lihua Ding

doi:10.1155/2019/9474273

Abstract

Gemcitabine-based chemotherapy is the first-line treatment for pancreatic cancer. However, chemoresistance is a major obstacle to drug efficacy, leading to poor prognosis. Little progress has been achieved although multiple mechanisms are investigated. Therefore, effective strategies are urgently needed to overcome drug resistance. Here, we demonstrate that the transcription factor GATA binding protein 1 (GATA1) promotes gemcitabine resistance in pancreatic cancer through antiapoptotic pathway. GATA1 is highly expressed in pancreatic ductal adenocarcinoma (PDAC) tissues, and GATA1 status is an independent predictor of prognosis and response to gemcitabine therapy. Further investigation demonstrates GATA1 is involved in both intrinsic and acquired gemcitabine resistance in PDAC cells. Mechanistically, we find that GATA1 upregulates Bcl-XL expression by binding to its promoter and thus induces gemcitabine resistance through enhancing Bcl-XL mediated antiapoptosis in vitro and in vivo. Moreover, in PDAC patients, Bcl-XL expression is positively correlated with GATA1 level and predicts clinical outcomes and gemcitabine response. Taken together, our results indicate that GATA1 is a novel marker and potential target for pancreatic cancer. Targeting GATA1 combined with Bcl-XL may be a promising strategy to enhance gemcitabine response.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with poor prognosis [1]
We found that GATA binding protein 1 (GATA1) was upregulated in PDAC patients and correlated with recurrence-free survival (RFS) and overall survival (OS), in patients treated with gemcitabine
These findings suggest that GATA1 expression is highly elevated in PDAC

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with poor prognosis [1]. Gemcitabine remains a standard chemotherapeutic agent for advanced pancreatic cancer and postsurgery adjuvant therapy [4]. The mechanisms of gemcitabine resistance include failure of drug uptake and metabolism, activation of DNA repair pathways, resistance to apoptosis, and change of tumor and stromal microenvironment [6]. Recent studies demonstrated that signaling pathways modulating proliferation, differentiation, apoptosis, invasion, and angiogenesis, including MAPK, PI3K/Akt, and NF-κB, directly or indirectly regulate gemcitabine sensitivity in PDAC cells [7,8,9,10]. Further understanding of pathways mediating gemcitabine chemoresistance is crucial for developing improved treatments and prolonging patients’ survival in pancreatic cancer

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Conclusion