AJP - GI AJP: Regulatory, Integrative and Comparative Physiology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
QUICK SEARCH:   [advanced]


     

Am J Physiol Gastrointest Liver Physiol (January 31, 2008). doi:10.1152/ajpgi.00411.2007
This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
294/4/G899    most recent
00411.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chow, J. Y. C.
Right arrow Articles by Carethers, J. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chow, J. Y. C.
Right arrow Articles by Carethers, J. M.
Submitted on September 12, 2007
Accepted on January 30, 2008

TGF{beta} Mediates PTEN Suppression and Cell Motility Through Calcium-Dependent PKC{alpha} 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 {beta} (TGF{beta}) suppresses growth via the TGF{beta}-SMAD pathway, but promotes growth in cancer cells with disrupted SMAD signaling and corresponds to an invasive phenotype. TGF{beta} 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{beta} modulation of PTEN was mediated by protein kinase C (PKC). We have previously demonstrated that SMAD4-null BxPC3 pancreatic cancer cells treated with TGF{beta}1 (10 ng/mL), suppressed PTEN expression and increased cell proliferation. TGF{beta}-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{beta}, and PTEN downregulation by TGF{beta} was specifically mediated by PKC{alpha}. In parallel, TGF{beta} rapidly induced an increase in intracellular calcium from internal cellular stores, consistent with subsequent PKC{alpha} activation. The TGF{beta}-induced increase in cell migration was blocked by knock down of PKC{alpha}. Thus, calcium-dependent PKC{alpha} mediates TGF{beta}-induced transcriptional downregulation of PTEN, and this pathway promotes cell migration in a SMAD4-null environment. The TGF{beta}-PKC{alpha}-PTEN cascade may be a key pathway for pancreatic cancer cells to proliferate and metastasize.




This article has been cited by other articles:


Home page
 FASEB J.Home page
J. Sun, R. D. Ramnath, R. Tamizhselvi, and M. Bhatia
Role of protein kinase C and phosphoinositide 3-kinase-Akt in substance P-induced proinflammatory pathways in mouse macrophages
FASEB J, April 1, 2009; 23(4): 997 - 1010.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
N. T. Ihle, R. Lemos Jr., P. Wipf, A. Yacoub, C. Mitchell, D. Siwak, G. B. Mills, P. Dent, D. L. Kirkpatrick, and G. Powis
Mutations in the Phosphatidylinositol-3-Kinase Pathway Predict for Antitumor Activity of the Inhibitor PX-866 whereas Oncogenic Ras Is a Dominant Predictor for Resistance
Cancer Res., January 1, 2009; 69(1): 143 - 150.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Visit Other APS Journals Online
Copyright © 1977 by the American Physiological Society.