GATA1 Promotes Gemcitabine Resistance in Pancreatic Cancer through Antiapoptotic Pathway

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.

Polymeric Chloroquine as an Effective Antimigration Agent in the Treatment of Pancreatic Cancer

“…Figure S2C shows the comparison of PCQ9 with standard chemotherapeutic agents gemcitabine and 5-fluorouracil (5-FU) in their ability to inhibit colony formation in KPC8060 cells. The PCQ9 effect on the colony formation is similar to that of 10 μM gemcitabine and 5-FU . Taken together with the cell migration results, PCQ9 is more effective compared to HCQ.…”

Repurposing of the ALK Inhibitor Crizotinib for Acute Leukemia and Multiple Myeloma Cells

“…Consequently, imbalanced GATA1 regulation is involved in certain hematological diseases [32]. Overexpression of GATA1 promoted chemotherapy resistance in acute megakaryocytic leukemia and in pancreatic cancer [33,34].…”

Overcoming Gemcitabine Resistance in Pancreatic Cancer Using the BCL-XL–Specific Degrader DT2216

“…A recent study showed that ABT263 increased the antitumor effect of prexasertib, a Chk1 inhibitor, by inducing apoptosis in pancreatic cancer cells via inhibition of BCL-X L but not BCL-2 (40). Furthermore, Zhang Z et al showed that GATA1 induced GEM resistance in pancreatic cancer cells through the upregulation of BCL-X L expression (41). Using the RxG CRISPR screening, we identified BCL-X L as the most common gene providing resistance to not only GEM, but also to other chemotherapeutics such as 5FU and NIR.…”