Oncotarget

Research Papers:

PHLPP negatively regulates cell motility through inhibition of Akt activity and integrin expression in pancreatic cancer cells

Alena J. Smith _, Yang-An Wen, Payton D. Stevens, Jingpeng Liu, Chi Wang and Tianyan Gao

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Oncotarget. 2016; 7:7801-7815. https://doi.org/10.18632/oncotarget.6848

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Abstract

Alena J. Smith1,2, Yang-An Wen1, Payton D. Stevens1,2, Jingpeng Liu1, Chi Wang1, Tianyan Gao1,2

1Markey Cancer Center, University of Kentucky, Lexington, KY, USA

2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA

Correspondence to:

Tianyan Gao, e-mail: tianyan.gao@uky.edu

Keywords: pancreatic cancer, cell migration, tumor suppressor, PHLPP, integrin

Received: August 06, 2015    Accepted: January 01, 2016    Published: January 08, 2016

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.


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