Submitted on September 12, 2007
Accepted on January 30, 2008
TGF
Mediates PTEN Suppression and Cell Motility Through Calcium-Dependent PKC
Activation in Pancreatic Cancer Cells
Jimmy Y. C. Chow1, Hui Dong2, Khai T Quach1, Phuoc Nam Van Nguyen3, Kevin Chen4, and John M. Carethers5*
1 Dept. of Medicine, University of California San Diego, San Diego, California, United States
2 Medicine, University of California, San Diego, San Diego, California, United States
3 Medicine, UCSD, SAN DIEGO, California, United States
4 Medicine, UCSD, La Jolla, California, United States
5 GI Section (111D), University of California, San Diego, San Diego, California, United States; Dept. of Medicine, University of California San Diego, San Diego, California, United States
* To whom correspondence should be addressed. E-mail: jcarethers{at}ucsd.edu.
Transforming growth factor 
(TGF) suppresses growth via the TGF-SMAD pathway, but promotes growth in cancer cells with disrupted SMAD signaling and corresponds to an invasive phenotype. TGF also downregulates the tumor suppressor, PTEN, that is rarely mutated in sporadic pancreatic cancer; this downregulation may mediate cell proliferation and invasiveness but the mechanism is unknown. Here, we examined if TGF modulation of PTEN was mediated by protein kinase C (PKC). We have previously demonstrated that SMAD4-null BxPC3 pancreatic cancer cells treated with TGF1 (10 ng/mL), suppressed PTEN expression and increased cell proliferation. TGF-treated cells were examined for PKC activation and it's coupling to PTEN expression, utilizing pharmacologic and knock down methods. Calcium mobilization and cell migration were also examined. In BxPC3 cells, only two PKC isoforms were activated by TGF, and PTEN downregulation by TGF was specifically mediated by PKC
. In parallel, TGF rapidly induced an increase in intracellular calcium from internal cellular stores, consistent with subsequent PKC activation. The TGF-induced increase in cell migration was blocked by knock down of PKC. Thus, calcium-dependent PKC mediates TGF-induced transcriptional downregulation of PTEN, and this pathway promotes cell migration in a SMAD4-null environment. The TGF-PKC-PTEN cascade may be a key pathway for pancreatic cancer cells to proliferate and metastasize.
