Numb/Notch/PLK1 signaling pathway mediated hyperglycemic memory in pancreatic cancer cell radioresistance and the therapeutic effects of metformin
Abstract
BACKGROUND
Diabetes mellitus has presented a positive role in the progression of pancreatic cancer and "Hyperglycemic memory" could be an important cause for diabetic damage. While limited information is available regarding the role of "hyperglycemic memory" in the pancreatic cancer and its radio-resistance. We therefore investigated correlation among hyperglycemic memory, Numb and metformin in pancreatic cancer radio-resistance.
METHODS
High glucose and hyperglycemic memory models were established in vitro and in vivo. Western blot, real-time PCR were accordingly used to detect Numb /Notch/ Polo-like kinase1 (PLK1) signaling at the level of molecular, cellular and experimental animal model, respectively. The apoptosis rate was evaluated by TUNEL assay and Capase-3 activity. The therapeutic effect of metformin was revealed by detecting the level of Numb / Notch /PLK1 through Western blot and real-time PCR.
RESULTS
Inactivation of Numb promotes the pancreatic cancer radio-resistance through hyperglycemic memory and metformin could suppress the radio-resistance by activating Numb in vitro and in vivo. In addition, PLK1 and Notch signaling pathway (Notch1, HEY1) elevated in pancreatic cancer radio-resistance condition, which was induced by hyperglycemic memory. Moreover, Numb overexpression or metformin could suppress Notch pathway to alleviate pancreatic cancer radio-resistance.
CONCLUSIONS
Our data demonstrated that Numb might be a promising target for the improvement of…
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