Abstract 4720: Protein kinase C alpha (PKCα) regulates PI3K/AKT signaling in endometrial cancer

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Endometrial cancer is the most common gynecological malignancy and the fourth most common cancer in women in the United States. Although loss of PTEN and deregulation of PI3K/AKT signaling has been implicated in approximately 90% of endometrial cancer cases, understanding of the molecular etiology of the disease remains limited. Our analysis of tissue from 448 endometrial cancer patients has determined that ∼60% of human tumors show reduced expression or loss of the signal transduction molecule PKCα. Loss of this enzyme is also seen in endometrial hyperplasias arising in mouse models carrying germline mutations of PTEN (PtenΔ4-5, PtenC124R and PtenG129E) or endometrial specific deletion of PTEN (Ptenpr-/−), indicating that loss of PKCα can be an early event in development of the disease. In patients, reduced expression of PKCα correlates with markers of disease aggressiveness, such as increased myometrial invasion and lymph node involvement, supporting a tumor suppressive role for the enzyme in the endometrium. This correlation is particularly marked in endometrioid, PTEN-mutant disease, pointing to a potential link between PKCα and PI3K/AKT signaling. The role of PKCα in endometrial cancer was further examined using a panel of 17 human endometrial cancer cell lines with varying expression of the kinase. Restoration of PKCα in cell lines lacking the enzyme blocked their ability to grow in soft agarose, further supporting a tumor suppressive role of the kinase in this tissue. Stimulation of cells that express PKCα with PKC agonists reduced phosphorylation/activation of AKT and promoted loss of downstream PI3K/AKT targets such as cyclin D1 and inhibitor of DNA binding 1 (Id1). Analysis of the PKC isozyme expression profile in these cells combined with the use of selective inhibitors pointed to PKCα as the mediator of the effect. The demonstration that PKC agonists failed to inhibit AKT signaling in cell lines that lack expression of PKCα, and that expression of exogenous PKCα restored the effect, confirmed the involvement of PKCα. The inhibition of AKT by PKCα is dependent on PP2A since okadaic acid and calyculin A, but not the PHLPP1/2 inhibitors NSC117079 and NSC45586, blocked the effect, a finding consistent with the ability of PKCα to inhibit AKT activity in PTEN mutant cell lines. Taken together, our study provides evidence that 1) loss of PKCα is a common and early event in endometrial cancer; 2) PKCα plays a crucial role in regulating AKT activation and growth promoting signaling molecules in endometrial cancer, and 3) effects of PKCα on AKT in endometrial cancer are mediated by PP2A. Given the importance of PI3K/AKT in the disease, these findings highlight the potential of PKCα signaling as a potential biomarker for disease risk and as a potential therapeutic target in endometrial cancer. Supported by NIH grants CA036727, CA016056, and DK60632. Citation Format: Alice H. Hsu, Kathryn J. Curry, Kang-Sup Shim, Peter Frederick, Carl Morrison, Baojing Chen, Subodh M. Lele, Takiko Daikoku, Sudhansu K. Dey, Gustavo Leone, Adrian R. Black, Jennifer D. Black. Protein kinase C alpha (PKCα) regulates PI3K/AKT signaling in endometrial cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4720. doi:10.1158/1538-7445.AM2015-4720