Molecular Mechanisms of PHLPP-Mediated Regulation in Colon Cancer

Colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer death in the United States. Despite significant progress made in recent years, the molecular mechanisms of tumor formation and progression are not well understood. Aberrant protein phosphorylation caused by dysregulation of important signaling pathways in cells is found to be associated with almost all kinds of cancer. Hyper-activation of one of these signaling pathways, namely the PI3K/Akt pathway, promotes cell growth and proliferation and suppresses cell death, thereby providing normal cells with necessary ammunitions to circumvent the body regulation to form tumors. Thus, abnormal activation of PI3K/Akt signaling is considered oncogenic (cause development of tumors). To offset this insult, the body produces natural defense proteins called tumor suppressors to turn off oncogenic signals and prevent the formation and progression of tumors. Recently, we identified a novel protein phosphatase PHLPP representing one of these tumor suppressors. PHLPP is located on the chromosomal locus (18q21.33) that encounters the most frequent loss of heterozygosity, an event commonly associated with cancer formation and progression in colorectal cancer. We have shown previously that PHLPP functions to terminate the oncogenic signals activated by the PI3K/Akt pathway by directly dephosphorylating and inactivating Akt, a key component of the pathway. However, the molecular mechanism underlying PHLPP-mediated negative regulation remains unknown in colorectal cancer. The long-term goal of this proposed study is to investigate the function of PHLPP as a tumor suppressor in colorectal cancer. We propose to identify signaling pathways downstream of Akt that regulated by PHLPP, and to investigate the functional consequences of PHLPP-mediated downregulation of Akt signaling. Furthermore, the role of PHLPP in tumorigenesis of colorectal cancer will be elucidated in vivo. We will define the relationship between loss of PHLPP expression and increased malignancy and aggressiveness of colorectal tumors in patients. The results from this study will shed lights on developing potential cancer therapy use PHLPP as a novel target.