PKCη is a negative regulator of AKT inhibiting the IGF-I induced proliferation.
The PI3K-AKT pathway is frequently activated in human cancers, including breast cancer, and its activation appears to be critical for tumor maintenance. Some malignant cells are dependent on activated AKT for their survival; tumors exhibiting elevated AKT activity show sensitivity to its inhibition, providing an Achilles heel for their treatment. Here we show that the PKCη isoform is a negative regulator of the AKT signaling pathway. The IGF-I induced phosphorylation on Ser473 of AKT was inhibited by the PKCη-induced expression in MCF-7 breast adenocarcinoma cancer cells. This was further confirmed in shRNA PKCη-knocked-down MCF-7 cells, demonstrating elevated phosphorylation on AKT Ser473. While PKCη exhibited negative regulation on AKT phosphorylation it did not alter the IGF-I induced ERK phosphorylation. However, it enhanced ERK phosphorylation when stimulated by PDGF. Moreover, its effects on IGF-I/AKT and PDGF/ERK pathways were in correlation with cell proliferation. We further show that both PKCη and IGF-I confer protection against UV-induced apoptosis and cell death having additive effects. Although the protective effect of IGF-I involved activation of AKT, it was not affected by PKCη expression, suggesting that PKCη acts through a different route to increase cell survival. Hence, our studies show that PKCη provides negative control on AKT pathway leading to reduced cell proliferation, and further suggest that its presence/absence in breast cancer cells will affect cell death, which could be of therapeutic value.
The Shraga Segal department of Microbiology and Immunology, Faculty of Health Science and the Cancer Research Center, Ben Gurion University of the Negev, Beer Sheva 84105, Israel.
Galit
G
Shahaf
Noa
N
Rotem-Dai
Gabriela
G
Koifman
Hadas
H
Raveh-Amit
Sigal A
SA
Frost
Etta
E
Livneh
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014466:Ultraviolet Rays
D007527:Isoenzymes; D010982:Platelet-Derived Growth Factor; D034741:RNA, Small Interfering; D012694:Serine; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; C081975:protein kinase C eta; D051058:Oncogene Protein v-akt; D011493:Protein Kinase C