The androgen receptor in the human prostate cancer cell line, LNCaP, mediates multihormonal regulation of both parathyroid hormone-related protein (PTHrP) and PSA genes

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 355-388-Sex Hormone Receptor Action & Reaction
Basic/Translational
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-370
Takao Susa*, Takashi Kajitani, Masayoshi Iizuka, Mimi Tamamori-Adachi and Tomoki Okazaki
Teikyo Univ Schl of Med, Tokyo, Japan
Uncontrolled expression of PTHrP is responsible for lethal hypercalcemia of malignancy. We have been characterizing PTHrP gene regulation in response to a series of steroid hormones and their cognate nuclear receptors (NRs). In human breast cancer MCF7 cells, we found suppression of PTHrP gene by complexes of a given steroid hormones and their cognate NR in common with an exception of DHT-AR partnership. DHT repressed PTHrP gene expression through ERa, but not AR.

In this study, we investigated whether such a disordered ligand-NR interaction observed in MCF7 cells also exists in other hormone-dependent cell line, human prostate cancer LNCaP cells.

Expression of PTHrP was suppressed and that of PSA was stimulated by vitamin D3, DHT, E2, dexamethasone and R5020 in LNCaP cells, respectively. Expression of both AR and VDR was much higher than that of GR or PR, while the amounts of ERa and ERb were negligible in these cells. Interestingly, knockdown experiments by using siRNA for AR, but not for other NRs, revealed that suppression of PTHrP and stimulation of PSA gene expression by all the above steroid hormones were similarly canceled out. It is well known that the AR gene in LNCaP cells has a point mutation (Thr-Ala877), resulting in a partial loss of AR's ligand specificity. We speculate that the AR in LNCaP mediated not only DHT-, but also E2- and R5020-induced gene regulations. On the other hand, there have been no reports indicating such a mutation leads to interaction between AR and either vitamin D3 or dexamethasone in these cells. Collectively, we raise a possibility that a mutated or non-mutated AR could elicit ligand-induced gene expression through a complex network of nuclear interwoven signaling cascades.

Nothing to Disclose: TS, TK, MI, MT, TO

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