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PROM2 promotes gemcitabine chemoresistance via activating the Akt signaling pathway in pancreatic cancer

Experimental & Molecular Medicine 2020년 52권 3호 p.1 ~ 1
 ( Li Wenbin ) - Sun Yat-Sen University Sun Yat-Sen Memorial Hospital Department of Hepatobiliary Pancreatic Surgery

 ( Zhu Yue ) - Sun Yat-Sen University Sun Yat-Sen Memorial Hospital Medical Research Center
 ( Zhang Kelin ) - Sun Yat-Sen University Sun Yat-Sen Memorial Hospital Medical Research Center
 ( Yu Xianhuan ) - Sun Yat-Sen University Sun Yat-Sen Memorial Hospital Department of Hepatobiliary Pancreatic Surgery
 ( Lin Haoming ) - Sun Yat-Sen University Sun Yat-Sen Memorial Hospital Department of Hepatobiliary Pancreatic Surgery
 ( Wu Wenrui ) - Sun Yat-Sen University Sun Yat-Sen Memorial Hospital Department of Hepatobiliary Pancreatic Surgery
 ( Peng Yaorong ) - Sun Yat-Sen University Sun Yat-Sen Memorial Hospital Department of Hepatobiliary Pancreatic Surgery
 ( Sun Jian ) - Sun Yat-Sen University Sun Yat-Sen Memorial Hospital Department of Hepatobiliary Pancreatic Surgery

Abstract


In recent years, the deoxycytidine analogue gemcitabine (2′,2′,-difluorodeoxycytidine) has become the first-line chemotherapeutic agent for patients with pancreatic cancer. However, due to the intrinsic resistance of pancreatic cancer cells, gemcitabine-based chemotherapy yields limited disease control, with >85% disease progression at 6 months from diagnosis. Therefore, elucidating the mechanisms of chemoresistance is a critical step in improving cancer therapy, especially for the treatment of pancreatic cancer. We show PROM2, a transmembrane glycoprotein, is ubiquitously upregulated in pancreatic cancer cell. We also found higher PROM2 expression is associated with shortened overall and disease-free survival times in patients diagnosed with pancreatic cancer. We provide evidence that PROM2 promotes chemoresistance to gemcitabine both in vivo and in vitro. Mechanistically, we demonstrate that PROM2 could directly interacted with Akt and activates the Akt signaling pathway, which thus inhibiting gemcitabine-induced apoptosis. As further evidence, we show PROM2 expression and Akt phosphorylation both promote gemcitabine chemoresistance, and cause poorer survival in clinical samples with pancreatic cancer. Combining gemcitabine with the Akt inhibitor MK-2206 facilitated significant tumor shrinkage and dramatically elevated the survival status in mice xenografted with pancreatic cancer cells. Our findings not only establish PROM2 as a novel positive regulator of the Akt signaling pathway and a candidate prognostic indicator of gemcitabine response, but also provide a neo-therapeutic approach for patients resistant to gemcitabine treatment.

키워드

Pancreatic cancer; Prognostic markers
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