The signal transduction mechanisms underlying progression to androgen-independent prostate cancer (PCa) are still poorly understood. In addition to the well-known role for androgen in development and progression of the disease, the phosphoinositide-3-kinase (PI3K) -Akt/protein kinase B (PKB) -> mTOR (mammalian target of rapamycin) pathway has recently been identified as an important regulator of prostate tumor cell growth and survival. The mechanisms of intersection of androgenic signaling with other signaling pathways, and in particular the PI3K/Akt/mTOR pathway, have not been clearly delineated, and in a number of respects are in dispute. We present evidence in this proposal that a major point of intersection between the androgen receptor (AR) and PI3K/Akt signaling is in the cholesterol-rich lipid raft component of the plasma membrane. We present several lines of evidence for this conclusion, including multiple independent observations that lipid raft membranes are sites of direct regulation of the Akt serine-threonine kinase, evidence that the AR can transit through this membrane compartment, and that AR and Akt form a ligand-dependent protein complex preferentially within lipid raft membranes. An important hypothesis obtained directly from our preliminary data is that androgen regulates Akt by direct interaction between AR and one or more phosphorylated forms of Akt, suggesting that the raft membrane is an important point of bifurcation for androgenic signals. In this proposal we will test this hypothesis by pursuing the following specific aims:
Aim 1. Determine how androgen regulates lipid raft-resident Akt.
Aim 2. Identify signaling pathways transmitted through lipid rafts, and signaling components present within rafts, that lie downstream of androgen and other AR activators. We believe these experiments will provide substantial new insight into the role of the AR, soluble factors other than androgen present in the tumor milieu, and cholesterol-rich membranes in PCa progression. They are also designed to identify new signaling proteins of potential relevance to PCa, thereby widening possibilities for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA112303-02
Application #
7017042
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Woodhouse, Elizabeth
Project Start
2005-03-01
Project End
2010-02-28
Budget Start
2006-03-13
Budget End
2007-02-28
Support Year
2
Fiscal Year
2006
Total Cost
$293,339
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Minciacchi, Valentina R; You, Sungyong; Spinelli, Cristiana et al. (2015) Large oncosomes contain distinct protein cargo and represent a separate functional class of tumor-derived extracellular vesicles. Oncotarget 6:11327-41
Minciacchi, Valentina R; Freeman, Michael R; Di Vizio, Dolores (2015) Extracellular vesicles in cancer: exosomes, microvesicles and the emerging role of large oncosomes. Semin Cell Dev Biol 40:41-51
Kim, Jayoung; Morley, Samantha; Le, Minh et al. (2014) Enhanced shedding of extracellular vesicles from amoeboid prostate cancer cells: potential effects on the tumor microenvironment. Cancer Biol Ther 15:409-18
Morley, Samantha; Hager, Martin H; Pollan, Sara G et al. (2014) Trading in your spindles for blebs: the amoeboid tumor cell phenotype in prostate cancer. Asian J Androl 16:530-5
Mukhopadhyay, N K; Kim, J; You, S et al. (2014) Scaffold attachment factor B1 regulates the androgen receptor in concert with the growth inhibitory kinase MST1 and the methyltransferase EZH2. Oncogene 33:3235-45
Solomon, Keith R; Allott, Emma H; Freeman, Michael R et al. (2013) Words of wisdom. Re: Dysregulation of cholesterol homeostasis in human prostate cancer through loss of ABCA1. Eur Urol 63:1128-9
Franz, M-C; Anderle, P; Bürzle, M et al. (2013) Zinc transporters in prostate cancer. Mol Aspects Med 34:735-41
Hager, Martin H; Morley, Samantha; Bielenberg, Diane R et al. (2012) DIAPH3 governs the cellular transition to the amoeboid tumour phenotype. EMBO Mol Med 4:743-60
Cinar, Bekir; Collak, Filiz Kisaayak; Lopez, Delia et al. (2011) MST1 is a multifunctional caspase-independent inhibitor of androgenic signaling. Cancer Res 71:4303-13
Pelton, Kristine; Di Vizio, Dolores; Insabato, Luigi et al. (2010) Ezetimibe reduces enlarged prostate in an animal model of benign prostatic hyperplasia. J Urol 184:1555-9

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