The Hsp90 inhibitor, 17‐AAG, prevents the ligand‐independent nuclear localization of androgen receptor in refractory prostate cancer cells

Saporita, Anthony J.; Ai, Junkui; Wang, Zhou

doi:10.1002/pros.20541

Cited by 71 publications

(66 citation statements)

References 42 publications

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“…Both lines underwent growth in response to a low concentration (50 pM) of the synthetic androgen R1881; how- VOL. 30,2010 FKBP51 AND PROSTATE CANCER 1245 ever, FKBP51 expression provided an advantage for cell growth in this assay (P Ͻ 0.001; Fig. 3B).…”

Section: Resultsmentioning

confidence: 88%

FKBP51 Promotes Assembly of the Hsp90 Chaperone Complex and Regulates Androgen Receptor Signaling in Prostate Cancer Cells

Yang

Gioeli³

et al. 2010

Molecular and Cellular Biology

144

124

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Prostate cancer progression to the androgen-independent (AI) state involves acquisition of pathways that allow tumor growth under low-androgen conditions. We hypothesized that expression of molecular chaperones that modulate androgen binding to AR might be altered in prostate cancer and contribute to progression to the AI state. Here, we report that the Hsp90 cochaperone FKBP51 is upregulated in LAPC-4 AI tumors grown in castrated mice and describe a molecular mechanism by which FKBP51 regulates AR activity. Using recombinant proteins, we show that FKBP51 stimulates recruitment of the cochaperone p23 to the ATP-bound form of Hsp90, forming an FKBP51-Hsp90-p23 superchaperone complex. In cells, FKBP51 expression promotes superchaperone complex association with AR and increases the number of AR molecules that undergo androgen binding. FKBP51 stimulates androgen-dependent transcription and cell growth, and FKBP51 is part of a positive feedback loop that is regulated by AR and androgen. Finally, depleting FKBP51 levels by short hairpin RNA reduces the transcript levels of genes regulated by AR and androgen. Because the superchaperone complex plays a critical role in determining the ligand-binding competence and transcription function of AR, it provides an attractive target for inhibiting AR activity in prostate cancer cells.

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Section: Resultsmentioning

confidence: 88%

FKBP51 Promotes Assembly of the Hsp90 Chaperone Complex and Regulates Androgen Receptor Signaling in Prostate Cancer Cells

Yang

Gioeli³

et al. 2010

Molecular and Cellular Biology

144

124

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“…In its inactive state, the AR is stabilized in the cytoplasm by a complex containing several chaperones including the heat shock protein 90 (Hsp90). In addition to the AR, Hsp90 client proteins also include Akt, Raf-1, src, Bcr-Abl, and HER2; therefore, inhibition of Hsp90 function theoretically should promote the degradation of its client proteins disrupting several pathways required for cell growth and the prevention of apoptosis (48). One such inhibitor of HSP90 is being tested in patients with CRPC.…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Castration-Resistant Prostate Cancer: Locking Up the Molecular Escape Routes

Attar¹,

Takimoto²,

Gottardis

2009

Clinical Cancer Research

187

159

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The understanding of the key role that androgens play on the normal and pathological physiology of the prostate guided the development of different therapies for the treatment of locally advanced or metastatic prostate cancer (PCa). These so-called androgen deprivation therapies include surgical or chemical castration, achieved by the administration of gonadotropin-releasing hormone analogs; inhibition of steroidogenic enzymes; and finally, blocking of the binding of androgens to their receptor (AR) by the use of antiandrogens. Despite an excellent initial response, in approximately 2 to 3 years, most of these patients will succumb to the castration resistant form of the disease. Remarkably, even in the presence of castration levels of circulating androgens, these tumors are still dependent on a functional AR, and several molecular mechanisms have been proposed to explain this phenomenon. These include: (1) gene amplification and increased expression of the AR mRNA and protein, (2) selection of mutations in the AR that confer broader ligand specificity, (3) changes in the ratios or expression between the AR and its coregulators, (4) increased expression of steroidogenic enzymes, and (5) up-regulation of cross-talk signal transduction pathways that can activate the AR in a ligand-independent manner. We will summarize how these molecular hypotheses are being tested in the clinic by the latest therapeutic modalities.

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“…GFP and HA-Calreticulin expression were determined by Western analysis using mouse anti-GFP polyclonal (Santa Cruz Biotechnology, Inc., Santa Cruz, CA) and mouse anti-HA monoclonal (Covance, Denver, PA) antibodies as described previously. 34 Stable transfection was done similarly as above. When colonies were approximately 3 mm in diameter, they were isolated either by pipette tip or through the use of a cloning ring.…”

Section: Cell Culture Colony Formation Assay and Transfectionmentioning

confidence: 99%

Suppressive Roles of Calreticulin in Prostate Cancer Growth and Metastasis

Alur

Nguyen

Eggener

et al. 2009

The American Journal of Pathology

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Calreticulin is an essential, multifunctional Ca 2؉ -binding protein that participates in the regulation of intracellular Ca 2؉ homeostasis, cell adhesion, and chaperoning. Calreticulin is abundantly expressed and regulated by androgens in prostate epithelial cells. Given the importance of both calreticulin in multiple essential cellular activities and androgens in prostate cancer, we investigated the possibility of a role for calreticulin in prostate cancer progression. Immunohistochemistry revealed the down-regulation of calreticulin in a subset of human prostate cancer specimens. Prostate cancer cells overexpressing exogenous calreticulin produced fewer colonies in both monolayer culture and soft agar. Furthermore, calreticulin overexpression also inhibited tumor growth in the orthotopic PC3 xenograft tumor model and macroscopic lung metastasis in the rat Dunning AT3.1 prostate tumor model. To address the potential mechanism of calreticulin suppression of prostate cancer, we generated calreticulin mutants with different functional domains deleted. The calreticulin mutants containing the P-domain, which binds to other endoplasmic reticulum chaperone proteins, were sufficient for the suppression of PC3 growth in colony formation assays. Overall , our data support the hypothesis that calreticulin inhibits growth and/or metastasis of prostate cancer cells and that this suppression requires the P-domain.

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The Hsp90 inhibitor, 17‐AAG, prevents the ligand‐independent nuclear localization of androgen receptor in refractory prostate cancer cells

Cited by 71 publications

References 42 publications

FKBP51 Promotes Assembly of the Hsp90 Chaperone Complex and Regulates Androgen Receptor Signaling in Prostate Cancer Cells

FKBP51 Promotes Assembly of the Hsp90 Chaperone Complex and Regulates Androgen Receptor Signaling in Prostate Cancer Cells

Castration-Resistant Prostate Cancer: Locking Up the Molecular Escape Routes

Suppressive Roles of Calreticulin in Prostate Cancer Growth and Metastasis

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