Abstract

): Research Plan: The main goal of this proposal is to define how the PTEN phosphatase acts to suppress tumor formation and to exploit this knowledge to design novel therapeutic approaches to prostate cancer. Our preliminary studies have established that PTEN expression is frequently lost in prostate cancer at the transcriptional level and that PTEN loss in tumor cells leads to excess cell survival signaling.
In Aim 1, we will test the role of membrane localization on PTEN function by determining the effect of membrane targeted mutants of PTEN.
In Aim 2, we will investigate the role of PTEN in mediating sensitivity to apoptosis induced by detachment from matrix, known as anoikis. We will characterize the effect of PTEN in sensitizing prostate tumor cells to anoikis and investigate the mechanisms of anoikis induction.
In Aim 3, we will characterize the effect of PTEN expression in sensitizing cancer cells to a p optotic stimuli in vitro and investigate the effect of PTEN on tumorigenicity and sensitivity to chemotherapy and androgen deprivation in vivo in a prostate cancer xenograft animal model. This project will test the hypothesis that reconstitution of PTEN expression will reverse resistance to m u ltiple apoptotic stimuli associated with prostate cancer cells and represents a novel strategy for enhancing the efficacy of prostate cancer treatment.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA085772-06
Application #
6863678
Study Section
Subcommittee G - Education (NCI)
Program Officer
Eckstein, David J
Project Start
2000-09-16
Project End
2005-08-31
Budget Start
2005-03-01
Budget End
2005-08-31
Support Year
6
Fiscal Year
2005
Total Cost
$65,104
Indirect Cost

  Institution

Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599

  Publications

Mahajan, Nupam P; Liu, Yuanbo; Majumder, Samarpan et al. (2007) Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation. Proc Natl Acad Sci U S A 104:8438-43
Boggess, John F; Zhou, Chunxiao; Bae-Jump, Victoria L et al. (2006) Estrogen-receptor-dependent regulation of telomerase activity in human endometrial cancer cell lines. Gynecol Oncol 103:417-24
Chen, Ye-Guang; Wang, Qiang; Lin, Shi-Lung et al. (2006) Activin signaling and its role in regulation of cell proliferation, apoptosis, and carcinogenesis. Exp Biol Med (Maywood) 231:534-44
Zhou, Chunxiao; Bae-Jump, Victoria L; Whang, Young E et al. (2006) The PTEN tumor suppressor inhibits telomerase activity in endometrial cancer cells by decreasing hTERT mRNA levels. Gynecol Oncol 101:305-10
Majumder, Samarpan; Liu, Yuanbo; Ford 3rd, O Harris et al. (2006) Involvement of arginine methyltransferase CARM1 in androgen receptor function and prostate cancer cell viability. Prostate 66:1292-301
Bae-Jump, Victoria L; Zhou, Chunxiao; Gehrig, Paola A et al. (2006) Rapamycin inhibits hTERT telomerase mRNA expression, independent of cell cycle arrest. Gynecol Oncol 100:487-94
Liu, Yuanbo; Majumder, Samarpan; McCall, Wesley et al. (2005) Inhibition of HER-2/neu kinase impairs androgen receptor recruitment to the androgen responsive enhancer. Cancer Res 65:3404-9
Mahajan, Nupam P; Whang, Young E; Mohler, James L et al. (2005) Activated tyrosine kinase Ack1 promotes prostate tumorigenesis: role of Ack1 in polyubiquitination of tumor suppressor Wwox. Cancer Res 65:10514-23
Gregory, Christopher W; Whang, Young E; McCall, Wesley et al. (2005) Heregulin-induced activation of HER2 and HER3 increases androgen receptor transactivation and CWR-R1 human recurrent prostate cancer cell growth. Clin Cancer Res 11:1704-12
Wu, Weidong; Silbajoris, Robert A; Whang, Young E et al. (2005) p38 and EGF receptor kinase-mediated activation of the phosphatidylinositol 3-kinase/Akt pathway is required for Zn2+-induced cyclooxygenase-2 expression. Am J Physiol Lung Cell Mol Physiol 289:L883-9

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