Prostate cancer is the most common malignancy among men in western countries. Prostate tumors initially respond well to androgen ablation or anti-androgen therapy, but eventually enter an androgen-independent stage with no effective therapy. Clearly, new therapeutic approaches are needed, and this will require a better understanding of the signaling events that control prostate tumorigenesis. Our laboratory has identified a new tumor suppressor, Par-4, which has pro-apoptotic activity and plays a role in human prostate tumorigenesis. Our preliminary results have demonstrated that Par-4 is lost in 60% of human prostate tumors, and that it binds and inhibits PKC?, consequently reducing NF-?B and Akt activation, and increasing cell death. Interestingly, tissue microarray analysis of human prostate carcinomas revealed a correlation between PKC? expression and increased Ki67 labeling indexes. Moreover, cancer gene-expression profiles comparing PKC? levels in different stages of human prostate neoplasias showed that PKC? expression was strongly correlated with a high degree of tumor aggressiveness. Therefore, the Par-4/PKC? complex appears to be a relevant candidate mediator of prostate tumorigenesis. In preliminary studies, we found that Par-4-/- mice developed benign hyperplasia and prostate intraepithelial neoplasias (PIN) that could progress to prostate adenocarcinomas when combined with PTEN heterozygous deletion. Therefore, Par-4 emerges as a novel tumor suppressor through its ability to impinge on two critical signaling pathways, NF-?B and Akt, likely through PKC?. The long-term goal of the studies proposed here is to unravel the signaling cascades involved in prostate cancer initiation and progression. This work will test the hypothesis that the loss of Par-4 in combination with PTEN haploinsufficiency triggers invasive prostate adenocarcinoma, and will determine the cellular and molecular signaling pathways that control that process. Advances in the understanding of these phenomena may uncover new perspectives on prostate carcinogenesis, and provide novel targets for prostate cancer prevention, diagnosis, and therapy. Therefore, in this proposal we will 1) test the hypothesis that Par-4 deficiency in combination with PTEN heterozygosity leads to the generation of invasive prostate cancer;and 2) determine the Par-4-mediated cellular and molecular mechanisms that are involved in prostate cancer progression in the context of PTEN haploinsufficiency. This work will increase our understanding of the mechanisms involved in the regulation of prostate carcinogenesis, and in the long term will provide the knowledge necessary for the development of novel, more specific, and thus less toxic, therapies for the treatment of prostate cancer.

Public Health Relevance

Prostate cancer is the most common type of cancer among men in western countries, and its incidence has increased in recent years. Currently, there is no efficient treatment because tumors develop resistance to the available drugs. This proposal is focused on understanding the in vivo role and mechanism of action of Par-4, a novel tumor suppressor, in the control of prostate tumorigenesis. This is a novel model system that will generate highly significant information regarding the identification of new molecular targets for the development of novel therapies and diagnostic approaches for prostate cancer. .

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Snyderwine, Elizabeth G
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Sanford-Burnham Medical Research Institute
La Jolla
United States
Zip Code
Valencia, Tania; Kim, Ji Young; Abu-Baker, Shadi et al. (2014) Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis. Cancer Cell 26:121-35
Hernandez, Eloy D; Lee, Sang Jun; Kim, Ji Young et al. (2014) A macrophage NBR1-MEKK3 complex triggers JNK-mediated adipose tissue inflammation in obesity. Cell Metab 20:499-511
Kim, Ji Young; Valencia, Tania; Abu-Baker, Shadi et al. (2013) c-Myc phosphorylation by PKCýý represses prostate tumorigenesis. Proc Natl Acad Sci U S A 110:6418-23
Linares, Juan F; Duran, Angeles; Yajima, Tomoko et al. (2013) K63 polyubiquitination and activation of mTOR by the p62-TRAF6 complex in nutrient-activated cells. Mol Cell 51:283-96
Ma, Li; Tao, Yongzhen; Duran, Angeles et al. (2013) Control of nutrient stress-induced metabolic reprogramming by PKC? in tumorigenesis. Cell 152:599-611
Moscat, Jorge; Diaz-Meco, Maria T (2012) p62: a versatile multitasker takes on cancer. Trends Biochem Sci 37:230-6
Diaz-Meco, Maria T; Moscat, Jorge (2012) The atypical PKCs in inflammation: NF-*B and beyond. Immunol Rev 246:154-67
Moscat, Jorge; Diaz-Meco, Maria T (2011) Feedback on fat: p62-mTORC1-autophagy connections. Cell 147:724-7
Linares, Juan F; Amanchy, Ramars; Greis, Kenneth et al. (2011) Phosphorylation of p62 by cdk1 controls the timely transit of cells through mitosis and tumor cell proliferation. Mol Cell Biol 31:105-17
Sengupta, Amitava; Duran, Angeles; Ishikawa, Eri et al. (2011) Atypical protein kinase C (aPKCzeta and aPKClambda) is dispensable for mammalian hematopoietic stem cell activity and blood formation. Proc Natl Acad Sci U S A 108:9957-62

Showing the most recent 10 out of 17 publications