Prostate Cancer Cells Increase Androgen Sensitivity by Increase in Nuclear Androgen Receptor and Androgen Receptor Coactivators; A Possible Mechanism of Hormone-Resistance of Prostate Cancer Cells

Abstract

Although androgen-hypersensitivity is one of the possible pathways of hormone-resistance in prostate cancer, the mechanisms of androgen-hypersensitivity are still largely unknown. Using androgen-hypersensitive prostate cancer cells LN-TR2, established from androgen-sensitive LNCaP cells by the long term treatment with tumor necrosis factor alpha, we explored the mechanisms of androgen-hypersensitivity in prostate cancer cells which may thus play a role in hormone-resistance. We examined the androgen receptor (AR) DNA sequence and the expression levels of AR and 8 AR cofactors in LNCaP and LN-TR2 cells. As a result, no novel mutation was developed in AR DNA in LN-TR2 cells. We observed higher expressions of nuclear AR upon androgen-treatment and 2 AR coactivators, ARA55 and TIF2, in LN-TR2 compared to LNCaP cells. An overexpression of ARA55 or TIF2 enhanced androgen-induced AR transcriptional activity in LNCaP cell. In the presence of those AR coactivators, AR activity was observed even at low concentrations of androgen. In 2 of 6 patients, the expression level of ARA55 was higher in cancer cells in hormone-resistant tumor than those in hormone-sensitive tumor. Taken together, our results suggest that prostate cancer cells change androgen-sensitivity by an overexpression of nuclear AR and AR coactivators, thus, resulting in transition from androgen-dependent to androgen-independent prostate cancer cells. An increase in nuclear AR and AR coactivators may cause androgen-hypersensitivity of prostate cancer cells and thus play a role in hormone-resistance, at least in some patients with prostate cancer.

Reconfiguring the AR-TIF2 Protein–Protein Interaction HCS Assay in Prostate Cancer Cells and Characterizing the Hits from a LOPAC Screen

“…5,12,13,[20][21][22]24,[30][31][32] SERMs and SARMs exhibit tissueselective behaviors because of the different expression levels and cohorts of coregulatory proteins found in different tissues. 7,14,32,35,37 In this article, we reconfigured the AR-TIF2…”

“…29 Prolonged AR localization on the promoters of AR target genes combined with elevated TIF2 recruitment has been implicated in the development of CRPC, and it was suggested that smallmolecule inhibitors of AR interactions with SRC coactivators might have therapeutic value. 5,12,13,21,22,24,[30][31][32] Differences in AR coregulator expression levels between CaP cell lines and normal tissues contribute to the observed variations in their androgen responsiveness. 33,34 For example, LnCaP cells express low levels of several AR corepressors with higher levels of coactivators such as TIF2, SRC-1, and FKBP4.…”

“…20 Elevated expression levels of several AR coregulators, including transcriptional intermediary factor 2 (TIF2/SRC-2), which is a member of the steroid receptor coactivator SRC/p160 family, have been associated with relapsed CaP. [3][4][5]12,13,[21][22][23][24] Cumulative evidence suggests that elevated TIF2 expression might be especially relevant to CRPC; TIF2 stabilizes AR-ligand binding, enhances receptor stability, facilitates AR N/C interactions, and promotes both the recruitment of chromatin remodeling coactivators and assembly of the transcriptional machinery on the promoters of AR target genes. 1,2,[25][26][27] There is a significant correlation between tumor TIF2 expression and CaP aggressiveness.…”

Targeting CDK9: a promising therapeutic opportunity in prostate cancer

“…As a result, PSA gene is constitutively expressed (Buchanan et al 2001). Briefly, AR activation can be attained through hypersensitivity to androgen (Fujimoto et al 2007) or agonist activity of alternative steroids or antiandrogens (Chan et al 2015). AR can also be activated through ectopic expression of androgens by PCa cells (Fig.…”

Regulation of tumor cell plasticity by the androgen receptor in prostate cancer

“…Several mechanisms for explaining CRPC progression have been proposed, including: altered functionality of the AR because of genetic alteration, which results in either hypersensitive (Visakorpi et al 1995, Waltering et al 2009), promiscuous (Fujimoto et al 2007), or constitutively activated (Dehm et al 2008) states; the intratumoral synthesis of androgens (Locke et al 2008); and altered growth factor and/or microenvironment signaling (Lai et al 2009, Sun et al 2012, Lubik et al 2013. Despite concerted efforts to develop pharmacological agents that are capable of suppressing AR signaling, progression is inevitable.…”