DNA-PKcs is important for Akt activation and gemcitabine resistance in PANC-1 pancreatic cancer cells

Hu, Hao; Gu, Yuanlong; Qian, Yi; Hu, Benshun; Zhu, Congyuan; Wang, Gaohe; Li, Jianping

doi:10.1016/j.bbrc.2014.08.059

Cited by 30 publications

(17 citation statements)

References 37 publications

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“…Emerging evidence suggests that the EMT is involved in cancer progression, and targeting the EMT can reverse the resistance of antitumor drugs (34). Furthermore, it was also confirmed in previous studies that hyperactivation of AKT signaling is involved in the chemoresistance of pancreatic cancer (35,36). The present findings demonstrated that the gemcitabine resistance of pancreatic cancer was due, in part, to the presence of YAP.…”

Section: Discussionsupporting

confidence: 87%

YAP overexpression promotes the epithelial-mesenchymal transition and chemoresistance in pancreatic cancer cells

Yuan

et al. 2015

Molecular Medicine Reports

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The expression of Yes-associated protein (YAP) has been reported to be dysregulated in pancreatic cancer. However, its contributions to tumor formation and progression remain to be elucidated. The present study demonstrated that YAP overexpression promoted the epithelial‑mesenchymal transition (EMT) in a manner associated with pancreatic cancer invasion in vitro. RNA interference‑mediated silencing of YAP attenuated cell invasion in vitro. Mechanistically, the present study demonstrated that YAP overexpression fosters pancreatic cancer progression by inducing the EMT in pancreatic cancer cells by activating the AKT cascade, which can counteract the effect of gemcitabine. These data suggested that the YAP acts synergistically to promote pancreatic cancer progression by hyperactivation of AKT signaling. The present study revealed YAP as a potential therapeutic target for pancreatic cancer and a biomarker for predicting gemcitabine treatment response.

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Section: Discussionsupporting

confidence: 87%

YAP overexpression promotes the epithelial-mesenchymal transition and chemoresistance in pancreatic cancer cells

Yuan

et al. 2015

Molecular Medicine Reports

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“…There are several signaling pathways, including Akt pathway, MAPK, Bcl-2, and MMP13 pathways, involved with gemcitabine chemoresistance in pancreatic cancer 13,44 . Though previous reports have suggested that MUC1, MUC4, and DNA-PKcs might enhance pancreatic cancer chemoresistance [45][46][47] , the underlying mechanism remains largely unknown. Our data suggest that PROM2 induces gemcitabine resistance via hyper-activation of the Akt signaling pathway, which inactivates BAD, Caspase-9, and eventually hinders the gemcitabine-induced apoptotic cascade.…”

Section: Discussionmentioning

confidence: 99%

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

Zhu

Zhang

et al. 2020

Exp Mol Med

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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 gemcitabineinduced 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.

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“…Liu et al [ 28 ] showed that the positive expression rate of p-AKT in pancreatic cancer was 83.8 %. The related research in most of pancreatic cancer, high expression of p-AKT, is correlated with poor prognosis [ 29 ], but there are also some research considered p-AKT-positive staining is correlated with better prognosis. We did not find any significant correlations between high p-AKT expression and certain clinicopathological findings.…”

Section: Discussionmentioning

confidence: 99%

Expression and significance of CD44 and p-AKT in pancreatic head cancer

Zhang

Leizhen

et al. 2015

World J Surg Onc

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BackgroundCD44 and phosphorylated AKT (p-AKT) is a potentially interesting prognostic marker and therapeutic target in pancreatic cancer. The expression of CD44 and p-AKT has been reported to correlate with poor prognosis of pancreatic cancer in most literatures. The purpose of this study is to investigate the roles of CD44 and p-AKT in pancreatic head cancer and their correlation with the prognosis of pancreatic head cancer patients.MethodsForty-eight pancreatic head cancer samples were collected dating from Jan. 2010 to Dec. 2012. Immunohistochemistry was applied to test the expression of CD44 and p-AKT in pancreatic head cancer. The clinical data of the patients were collected including their gender, age, the histology and location, lymph node metastasis, and so on. The correlation between the CD44 expression and the clinicopathological factors of patients with pancreatic head cancer was analyzed by the software SPSS 13.0.ResultsThe positive rates of CD44 and p-AKT expression in the samples were 64.6 and 29.2 %, respectively. There was a significant difference between the CD44 expression and the pancreatic cancer’ T staging, tumor node metastasis (TNM) staging, lymph node metastasis (P < 0.05). The Cox proportional hazard model showed that CD44 and lymph node metastasis were independent prognostic factors.ConclusionsCD44 was related to the distant metastasis and aggressive malignant behaviors of pancreatic head cancer.

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DNA-PKcs is important for Akt activation and gemcitabine resistance in PANC-1 pancreatic cancer cells

Cited by 30 publications

References 37 publications

YAP overexpression promotes the epithelial-mesenchymal transition and chemoresistance in pancreatic cancer cells

YAP overexpression promotes the epithelial-mesenchymal transition and chemoresistance in pancreatic cancer cells

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

Expression and significance of CD44 and p-AKT in pancreatic head cancer

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