Abstract
Pancreatic adenocarcinoma is currently the fourth leading cause for cancer-related mortality. Malignant progression of pancreatic cancer depends not only on rapid proliferation of tumor cells but also on increased cell motility. In this study, we showed that increased PHLPP expression significantly reduced the rate of migration in pancreatic ductal adenocarcinoma (PDAC) cells whereas knockdown of PHLPP had the opposite effect. In addition, cell motility at the individual cell level was negatively regulated by PHLPP as determined using time-lapse imaging. Interestingly, the expression of β1 and β4 integrin proteins were decreased in PHLPP overexpressing cells and increased in PHLPP knockdown cells whereas the mRNA levels of integrin were not altered by changes in PHLPP expression. In determining the molecular mechanism underlying PHLPP-mediated regulation of integrin expression, we found that inhibition of lysosome activity rescued integrin expression in PHLPP overexpressing cells, thus suggesting that PHLPP negatively controls cell motility by inhibiting Akt activity to promote lysosome-dependent degradation of integrins. Functionally, the increased cell migration observed in PHLPP knockdown cells was effectively blocked by the neutralizing antibodies against β1 or β4 integrin. Taken together, our study identified a tumor suppressor role of PHLPP in suppressing cell motility by negatively regulating integrin expression in pancreatic cancer cells.
Highlights
Pancreatic adenocarcinoma is the fourth leading cause of cancer related deaths in the United States, despite being the ninth most diagnosed cancer in men and the eleventh in women
To determine if PHLPP serves as a tumor suppressor in human pancreatic cancer, we established stable cell lines overexpressing PHLPP1 or PHLPP2 in Panc-1 cells, which express very low levels of endogenous PHLPPs
Consistent with previous reports on the tumor suppressor function of PHLPP in other cancer types [13, 15,16,17,18], our results here provide the initial evidence that PHLPP is capable of inhibiting both Akt and MEK/ERK signaling in pancreatic cancer cells
Summary
Pancreatic adenocarcinoma is the fourth leading cause of cancer related deaths in the United States, despite being the ninth most diagnosed cancer in men and the eleventh in women. It has been shown that overexpression of integrin α6β4 promotes migration and invasion of pancreatic cancer cells and is associated with the progression of PDAC [5, 6]. Nitsche et al discovered that there is a stage-dependent downregulation of PHLPP in pancreatic cancer patient specimens, suggesting a tumor suppressor role of PHLPP in pancreatic cancer [14]. It remains unknown whether loss of PHLPP expression promotes cancer cell migration in pancreatic cancer.
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