Reddy G Prem Veer, Barrack Evelyn R, Dou Q Ping, Menon Mani, Pelley Ronald, Sarkar Fazlul H, Sheng Shijie
Vattikuti Urology Institute, Henry Ford Hospital, Detroit, Michigan 48202, USA.
J Cell Biochem. 2006 Aug 15;98(6):1408-23. doi: 10.1002/jcb.20927.
Prostate cancer cells rely on androgen receptor (AR) for proliferation and survival. Therefore, curing prostate cancer will require elimination of AR. Although androgen is the natural ligand that activates AR, AR activity is also subject to regulation by growth factor/growth factor receptor-stimulated signaling pathways that control the cell cycle. Cell cycle regulatory proteins and protein kinases in signaling pathways affected by growth factors can lead to AR activation in the absence of androgen. While downstream signaling proteins such as cyclins, cyclin-dependent kinases (CDKs), and pRB can modulate AR activity, upstream signaling pathways involving protein kinases such as mitogen-activated protein kinases, protein kinase A, and protein kinase B/Akt can affect post-translational modification of AR to affect not only AR function but also AR stability. Calcium and calmodulin (CaM), essential for proliferation and viability of a number of cells, including prostate cancer cells, play an important role in AR expression, stability, and function. CaM affects AR partly by interacting directly with AR and partly by activating protein kinases such as Akt and DNA-PK that can phosphorylate AR. The ubiquitin/26S proteasome pathway responsible for timely destruction of cell cycle regulatory proteins whose levels impede cell cycle progression also induces AR expression by activating NF-kappaB, and promotes AR activity by participating in the assembly of an AR transcription complex. Maspin, a serine protease inhibitor that is known mostly for its role as a tumor suppressor can also regulate AR intracellular localization and function by competing with AR for binding to the chaperone protein Hsp90 and co-repressor HDAC1, respectively. This perspective reviews the experimental evidence implicating these diverse cellular processes in AR expression, stability, and/or function, and presents a rationale for disrupting these cellular processes as a viable option for the treatment of both the hormone-sensitive and the hormone-insensitive prostate cancer.
前列腺癌细胞的增殖和存活依赖雄激素受体（AR）。因此，治愈前列腺癌需要消除AR。虽然雄激素是激活AR的天然配体，但AR的活性也受到控制细胞周期的生长因子/生长因子受体刺激信号通路的调节。生长因子影响的信号通路中的细胞周期调节蛋白和蛋白激酶可导致在无雄激素的情况下AR激活。虽然细胞周期蛋白、细胞周期蛋白依赖性激酶（CDK）和pRB等下游信号蛋白可调节AR活性，但涉及丝裂原活化蛋白激酶、蛋白激酶A和蛋白激酶B/Akt等蛋白激酶的上游信号通路可影响AR的翻译后修饰，不仅影响AR功能，还影响AR稳定性。钙和钙调蛋白（CaM）对包括前列腺癌细胞在内的许多细胞的增殖和活力至关重要，在AR表达、稳定性和功能中起重要作用。CaM部分通过直接与AR相互作用，部分通过激活可使AR磷酸化的Akt和DNA-PK等蛋白激酶来影响AR。负责及时破坏其水平阻碍细胞周期进程的细胞周期调节蛋白的泛素/26S蛋白酶体途径也通过激活核因子κB诱导AR表达，并通过参与AR转录复合物的组装促进AR活性。Maspin是一种丝氨酸蛋白酶抑制剂，主要因其作为肿瘤抑制因子的作用而闻名，它还可分别通过与AR竞争结合伴侣蛋白Hsp90和共抑制因子HDAC1来调节AR的细胞内定位和功能。本文综述了涉及这些不同细胞过程与AR表达、稳定性和/或功能相关的实验证据，并提出破坏这些细胞过程作为治疗激素敏感型和激素不敏感型前列腺癌的可行选择的理论依据。
