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PROM2 promotes gemcitabine chemoresistance via activating the Akt signaling pathway in pancreatic cancer.
Experimental & Molecular Medicine ( IF 9.5 ) Pub Date : 2020-03-02 , DOI: 10.1038/s12276-020-0390-4 Wenbin Li 1, 2 , Yue Zhu 2, 3 , Kelin Zhang 2, 4 , Xianhuan Yu 1, 2 , Haoming Lin 1, 2 , Wenrui Wu 1, 2 , Yaorong Peng 1, 2 , Jian Sun 1, 2
Experimental & Molecular Medicine ( IF 9.5 ) Pub Date : 2020-03-02 , DOI: 10.1038/s12276-020-0390-4 Wenbin Li 1, 2 , Yue Zhu 2, 3 , Kelin Zhang 2, 4 , Xianhuan Yu 1, 2 , Haoming Lin 1, 2 , Wenrui Wu 1, 2 , Yaorong Peng 1, 2 , Jian Sun 1, 2
Affiliation
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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.
中文翻译：
PROM2 通过激活胰腺癌中的 Akt 信号通路促进吉西他滨化疗耐药。
近年来，脱氧胞苷类似物吉西他滨（2',2',-二氟脱氧胞苷）已成为胰腺癌患者的一线化疗药物。然而，由于胰腺癌细胞的内在耐药性，基于吉西他滨的化疗对疾病的控制有限，在诊断后 6 个月内疾病进展超过 85%。因此，阐明化疗耐药的机制是改善癌症治疗，尤其是胰腺癌治疗的关键步骤。我们显示 PROM2 是一种跨膜糖蛋白，在胰腺癌细胞中普遍上调。我们还发现更高的 PROM2 表达与被诊断患有胰腺癌的患者的总体和无病生存时间缩短有关。我们提供的证据表明 PROM2 在体内和体外都促进了对吉西他滨的化学抗性。从机制上讲，我们证明 PROM2 可以直接与 Akt 相互作用并激活 Akt 信号通路，从而抑制吉西他滨诱导的细胞凋亡。作为进一步的证据，我们显示 PROM2 表达和 Akt 磷酸化都促进了吉西他滨的化学抗性，并导致胰腺癌临床样本的存活率降低。将吉西他滨与 Akt 抑制剂 MK-2206 结合使用可促进显着的肿瘤缩小，并显着提高异种移植胰腺癌细胞的小鼠的存活状态。我们的研究结果不仅将 PROM2 确立为 Akt 信号通路的新型正调节因子和吉西他滨反应的候选预后指标，
更新日期：2020-04-24
中文翻译：
PROM2 通过激活胰腺癌中的 Akt 信号通路促进吉西他滨化疗耐药。
近年来，脱氧胞苷类似物吉西他滨（2',2',-二氟脱氧胞苷）已成为胰腺癌患者的一线化疗药物。然而，由于胰腺癌细胞的内在耐药性，基于吉西他滨的化疗对疾病的控制有限，在诊断后 6 个月内疾病进展超过 85%。因此，阐明化疗耐药的机制是改善癌症治疗，尤其是胰腺癌治疗的关键步骤。我们显示 PROM2 是一种跨膜糖蛋白，在胰腺癌细胞中普遍上调。我们还发现更高的 PROM2 表达与被诊断患有胰腺癌的患者的总体和无病生存时间缩短有关。我们提供的证据表明 PROM2 在体内和体外都促进了对吉西他滨的化学抗性。从机制上讲，我们证明 PROM2 可以直接与 Akt 相互作用并激活 Akt 信号通路，从而抑制吉西他滨诱导的细胞凋亡。作为进一步的证据，我们显示 PROM2 表达和 Akt 磷酸化都促进了吉西他滨的化学抗性，并导致胰腺癌临床样本的存活率降低。将吉西他滨与 Akt 抑制剂 MK-2206 结合使用可促进显着的肿瘤缩小，并显着提高异种移植胰腺癌细胞的小鼠的存活状态。我们的研究结果不仅将 PROM2 确立为 Akt 信号通路的新型正调节因子和吉西他滨反应的候选预后指标，
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