TGF-beta mediates PTEN suppression and cell motility through calcium-dependent PKC-alpha activation in pancreatic cancer cells.
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 whether TGF-beta modulation of PTEN was mediated by protein kinase C (PKC). We have previously demonstrated that SMAD4-null BxPc-3 pancreatic cancer cells treated with TGF-beta1 (10 ng/ml) suppressed PTEN expression and increased cell proliferation. TGF-beta-treated cells were examined for PKC activation and its coupling to PTEN expression, utilizing pharmacological and knockdown methods. Calcium mobilization and cell migration were also examined. In BxPc-3 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 cytoplasmic free calcium from intracellular stores, consistent with subsequent PKC-alpha activation. The TGF-beta-induced increase in cell migration was blocked by knockdown 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.
Chow
Jimmy Y C
JY
Division of Gastroenterology, Department of Medicine, University of California San Diego, San Diego, California, USA.
Dong
Hui
H
Quach
Khai T
KT
Van Nguyen
Phuoc Nam
PN
Chen
Kevin
K
Carethers
John M
JM
D002118:Calcium / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D015536:Down-Regulation; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004789:Enzyme Activation; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051901:Smad4 Protein / Q000172:deficiency / Q000378:metabolism; D014158:Transcription, Genetic; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D000099293:Protein Kinase C-lambda
D002118:Calcium; D002227:Carbazoles; D002614:Chelating Agents; D004533:Egtazic Acid; D007211:Indoles; D007527:Isoenzymes; D051059:PTEN Phosphohydrolase; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D051901:Smad4 Protein; D053773:Transforming Growth Factor beta1; D000099293:Protein Kinase C-lambda; C497796:SMAD4 protein, human; C081021:Go 6976; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; C494929:PTEN protein, human