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, Tianyan Gao

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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.

Original languageEnglish
Pages (from-to)7801-7815
Number of pages15
JournalOncotarget
Volume7
Issue number7
DOIs
StatePublished - 2016

Bibliographical note

Funding Information:
This work was supported by NIH R01CA133429 (TG). The studies were supported by Biostatistics Shared Resources of the University of Kentucky Markey Cancer Center (P30CA177558). We thank Garretson Epperly for providing technical support for this study.

Keywords

  • Cell migration
  • Integrin
  • PHLPP
  • Pancreatic cancer
  • Tumor suppressor

ASJC Scopus subject areas

  • Oncology

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