PubMed · 8215337
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K Yokoyama. Mediated microbiosensors.. https://doi.org/10.1007/bf02918523
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BACKGROUND: Androgen receptor (AR) is the key molecule in androgen-refractory prostate cancer. Despite androgen ablative conditions, AR remains active and is necessary for the growth of androgen-refractory prostate cancer cells. Nuclear localization of AR is a prerequisite for its transcriptional activation. We examined AR localization in androgen-dependent and androgen-refractory prostate cancer cells. METHODS AND RESULTS: We demonstrate increased nuclear localization of a GFP-tagged AR in the absence of hormone in androgen-refractory C4-2 cells compared to parental androgen-sensitive human prostate cancer LNCaP cells. Analysis of AR mutants impaired in ligand-binding indicates that the nuclear localization of AR in C4-2 cells is truly androgen-independent. The hsp90 inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AAG), inhibits basal PSA expression and disrupts the ligand-independent nuclear localization of AR at doses much lower than required to inhibit androgen-induced nuclear import. CONCLUSIONS: Hsp90 is a key regulator of ligand-independent nuclear localization and activation of AR in androgen-refractory prostate cancer cells.
We investigated the mechanism by which activation of the Ah receptor by dioxin (TCDD) was accompanied by rapid activation of c-Src kinase activity. A Western blotting analysis showed that such action of TCDD in MCF10A cells could effectively be suppressed by treatment with a specific inhibitor of Src family kinase, PP-2, as judged by Western blot detection of the active form of Src protein, indicating that Src kinase is directly activated by TCDD. Such an event, occurring within 10-30 min of the addition of TCDD, is also accompanied by simultaneous translocation of both Src and cdc37 proteins from cytosol into the 100,000 x g membrane fraction containing the plasma membrane. By dissociating the cytosolic Src-cdc37-HSP90 complex with 17 nM geldanamycin, an optimum concentration for affecting this cytosolic cdc37 complex, but not the cytosolic Ah receptor complex, we could show that the action of TCDD in activating c-Src and cdc37 was abolished, but not its action on CYP1A1. The important role of cdc37 in the action of TCDD-induced activation of c-Src was also confirmed by blocking cdc37 gene translation with the antisense oligonucleotide treatment as well as the siRNA preparation designed to silence cdc37 expression. To understand the functional meaning of the disruption of the Src-cdc37-HSP90 complex by 17 nM geldanamycin at the cellular level, we investigated its effect on TCDD-induced anti-apoptotic action. The results showed that geldanamycin at this concentration could also abolish this cellular effect of TCDD. Interestingly, such a role of cdc37 in mediating the action of TCDD appears to be limited to activation of c-Src kinase, but not kinases associated with activation of NFkB, C/EBPalpha, or ERK. Together, these observations support the hypothesis that there is a specific coordination between the activation of the cytosolic Ah receptor and the c-Src- and cdc37-containing HSP90 complex.
[structure: see text] Hsp90 has recently emerged as a promising biological target for treatment of cancer. Herbimycin A and other members of the benzoquinoid ansamycin class of natural products are known to inhibit Hsp90 activity. The total synthesis of herbimycin A was achieved from the commercially available Roche ester 1 by using allylmetals to control the stereogenic centers at C6, C7, C10, C11, and C12 and a ring-closing metathesis to control the (Z)-double bond of the (E,Z)-dienic moiety.