title: PTEN sensitizes MDA-MB-468 cells to inhibition of MEK/Erk signaling for the blockade of cell proliferation.
abstract: Phosphatase and tensin homolog (PTEN) is a tumor suppressor that inhibits PI3K/Akt signaling. To examine the effect of PTEN on breast cancer cell proliferation, we expressed PTEN in MDA-MB-468 cells (MDA-MB-468 PTEN) by retroviral infection and tested the cell proliferation rate. We found that the growth rate of MDA-MB-468 PTEN cells was significantly lower than that of MDA-MB-468 control vector cells (MDA-MB-468 vec). When the PI3K/Akt signaling inhibitor LY294002 and the MEK/Erk signaling inhibitor U0126 were applied, LY294002 reduced cell proliferation in MDA-MB-468 PTEN and MDA-MB-468 vec by 20%, while U0126 led to a >60% reduction in MDA-MB-468 PTEN and a 20% reduction in MDA-MB-468 vec cells. FACS analysis demonstrated that the subG0/G1 apoptotic fraction was significantly increased in MDA-MB-468 PTEN cells after U0126 treatment, while LY294002 treatment in both cell lines and U0126 treatment in MDA-MB-468 vec cells led to a modest increase in the apoptotic fraction. This phenomenon was accompanied by the down-regulation of p-Erk. p-Erk levels were significantly lower after U0126 treatment in MDA-MB-468 PTEN cells. Similar results were observed in MDA-MB-231 cells, which express endogenous PTEN. The growth of MDA-MB-231 cells was significantly inhibited after U0126 treatment, compared to LY294002, while PTEN-null ZR-75-1 cells did not show increased sensitivity to U0126 over LY294002. Taken together, these findings suggest that blockade of PI3K/Akt signaling by PTEN may render breast cancer cells more dependent on the MEK/Erk pathway for their proliferation and survival.
authors.affiliation: Department of Life Science, College of Natural Sciences, Hanyang University, Seoul 133-791, Korea.
authors.forename: Kibeom
authors.initials: K
authors.lastname: Jang
authors.forename: Minsoon
authors.initials: M
authors.lastname: Kim
authors.forename: Hye-Sook
authors.initials: HS
authors.lastname: Seo
authors.forename: Incheol
authors.initials: I
authors.lastname: Shin
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002070:Butadienes / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D002070:Butadienes; D002867:Chromones; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D009025:Morpholines; D009570:Nitriles; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494929:PTEN protein, human