Androgen Receptor Splice Variant 7 Drives the Growth of Castration Resistant Prostate Cancer without Being Involved in the Efficacy of Taxane Chemotherapy.
Androgen Receptor Splice Variant 7 Drives the Growth of Castration Resistant Prostate Cancer without Being Involved in the Efficacy of Taxane Chemotherapy.
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DOI：
10.3390/jcm7110444
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发表时间：
2018-11-16
影响因子：
3.9
通讯作者：
Nakatani T
中科院分区：
文献类型：
--
作者：
Shimizu Y;Tamada S;Kato M;Hirayama Y;Takeyama Y;Iguchi T;Sadar MD;Nakatani T
雄激素受体(AR)剪接变异体7(AR-V7)的表达与去势耐受前列腺癌(CRPC)的发生发展有关。然而，AR-V7的表达与紫杉烷类药物(如多西紫杉醇或卡氮紫杉醇)的耐药性之间的潜在联系尚未得到明确证明。为了解决这个问题，我们使用了LNCaP95-DR细胞，这些细胞表达AR-V7，并对苯扎鲁胺和多西紫杉醇表现出耐药性。有趣的是，LNCaP95-DR细胞对卡氮紫杉醇表现出交叉耐药。此外，这些细胞的P-糖蛋白(P-gp)水平增加，它们对多西紫杉醇和卡巴紫杉醇的敏感性可通过P-gp拮抗剂泰奎达恢复。结果表明P-gp介导了多西紫杉醇和卡氮紫杉醇之间的交叉耐药。虽然LNCaP95-DR细胞AR-V7及其靶基因(UBE2C、CDC20)的表达增加，但AR-V7基因的敲除并不能恢复对多西紫杉醇或卡氮紫杉醇的敏感性。然而，尽管对多西紫杉醇和卡巴紫杉醇耐药，AR氨基末端结构域(NTD)拮抗剂EPI-002对LNCaP95-DR细胞的增殖具有抑制作用，与亲代LNCaP95细胞的作用相似。另一方面，苯扎鲁胺对两种细胞株的增殖均无影响。综上所述，我们的结果提示EPI-002可能是治疗AR-V7驱动的CRPC的一种选择，这种CRPC对紫杉烷类药物具有耐药性。
Expression of androgen receptor (AR) splice variant 7 (AR-V7) has been identified as the mechanism associated with the development of castration-resistant prostate cancer (CRPC). However, a potential link between AR-V7 expression and resistance to taxanes, such as docetaxel or cabazitaxel, has not been unequivocally demonstrated. To address this, we used LNCaP95-DR cells, which express AR-V7 and exhibit resistance to enzalutamide and docetaxel. Interestingly, LNCaP95-DR cells showed cross-resistance to cabazitaxel. Furthermore, these cells had increased levels of P-glycoprotein (P-gp) and their sensitivity to both docetaxel and cabazitaxel was restored through treatment with tariquidar, a P-gp antagonist. Results generated demonstrated that P-gp mediated cross-resistance between docetaxel and cabazitaxel. Although the LNCaP95-DR cells had increased expression of AR-V7 and its target genes (UBE2C, CDC20), the knockdown of AR-V7 did not restore sensitivity to docetaxel or cabazitaxel. However, despite resistance to docetaxel and carbazitaxel, EPI-002, an antagonist of the AR amino-terminal domain (NTD), had an inhibitory effect on the proliferation of LNCaP95-DR cells, which was similar to that achieved with the parental LNCaP95 cells. On the other hand, enzalutamide had no effect on the proliferation of either cell line. In conclusion, our results suggested that EPI-002 may be an option for the treatment of AR-V7-driven CRPC, which is resistant to taxanes.
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DOI：
10.1158/1078-0432.ccr-08-2660
发表时间：
2009-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Knudsen KE;Scher HI
通讯作者：
Scher HI
影响因子：
3
作者：
Ferron, Geraldine M.;Dai, Yang;Semiond, Dorothee
通讯作者：
Semiond, Dorothee
影响因子：
120.1
作者：
Galsky, Matthew D.;Dritselis, Argyris;Oh, William K.
通讯作者：
Oh, William K.
影响因子：
50.3
作者：
Domingo-Domenech J;Vidal SJ;Rodriguez-Bravo V;Castillo-Martin M;Quinn SA;Rodriguez-Barrueco R;Bonal DM;Charytonowicz E;Gladoun N;de la Iglesia-Vicente J;Petrylak DP;Benson MC;Silva JM;Cordon-Cardo C
通讯作者：
Cordon-Cardo C
影响因子：
2.8
作者：
Kuroda, Kenji;Liu, He;Bander, Neil H.
通讯作者：
Bander, Neil H.