去势抵抗性前列腺癌增殖转移机制及其干预治疗

发布时间：2018-02-14 03:48

本文关键词： 前列腺癌雄激素受体脂肪酸合成酶肿瘤干/祖细胞组蛋白-赖氨酸 N-甲基转移酶 ASC-J9 雄激素剥夺治疗　出处：《天津医科大学》2014年博士论文　论文类型：学位论文

【摘要】：前列腺癌是欧美地区男性发病率最高的恶性肿瘤,在我国,随着生活习惯,饮食结构的改变已经年龄结构老龄化等,前列腺癌的发病率正以每年10%的速率逐年上升。雄激素受体信号通路在前列腺癌的发生发展中起着至关重要的作用,传统的的前列腺癌法案就是雄激素剥夺治疗(androgen deprition treatment, ADT),包括药物抗雄激素以及手术去势,就是以阻止雄激素结合到雄激素受体上的方式来抑制肿瘤的生长。这一方案至今仍是前列腺癌的主要治疗手段。然后,传统的抗雄治疗并不能完全的抑制前列腺癌的进程,大多数前列腺癌患者在经过ADT治疗之后都会以非激素依赖的方式复发。在前列腺癌中,雄激素受体(androgen receptor, AR)对于各种细胞死亡的方式的调节各不相同,因此对前列腺癌给予ADT治疗对各种细胞死亡的影响也不尽相同。本研究首先研究了AR在Entosis中的调节作用,其作用机制主要是通过Rho/ROCK通路来促进细胞的Entosis。本研究完善了AR对于前列腺癌细胞死亡的调节。至今为止,在前列腺癌中,共有五种细胞死亡的方式被报道,而ADT会促进前列腺癌细胞的凋亡、坏死和自噬,却减少了前列腺癌细胞的失巢性凋亡和侵入性死亡。前三者与前列腺癌细胞的生长相关,而后二者则与肿瘤细胞的侵袭相关。这就导致了ADT会抑制前列腺癌的生长,却增加了肿瘤的侵袭性。作为对AR在前列腺癌细胞生长调节的补充,进一步解释了AR在前列腺癌中的双重作用。在上述理论的基础上,通过进一步的研究,本课题发现ADT在去势条件下,ADT并不能抑制脂肪酸代谢的关键酶FASN和肿瘤干／祖细胞,揭示了为什么ADT对于去势抵抗性前列腺癌效果不佳,且导致肿瘤更加具有侵袭性。再进一步,本研究提供了一种新型的抗前列腺癌药物ASC-J9。通过对比研究发现,这一药物比传统ADT(如Casodex和MDV3100)更加具有优势。首先,ASC-J9可以在激素依赖期的前列腺癌中通过AR通路(ASC-J9-AR-SREBP1-FASN)来抑制肿瘤进展,且效果比传统ADT更强；其次,在去势抵抗期的前列腺癌中(或在AR表达阴性的前列腺组织中),ASC-J9可以通过非AR通路(ASC-J9-PI3K/AKT-SREBP1-FASN)来抑制肿瘤进展；最后,ASC-J9可以通过抑制肿瘤干／祖细胞来从更深的层次抑制肿瘤的进展。ASC-J9的这些优势使其对前列腺癌具有比当前ADT药物更好的治疗效果,是一种可能的下一代抗前列腺癌药物治疗的选择。
[Abstract]:Prostate cancer is the most common malignant tumor in Europe and America. In our country, with the change of living habits and dietary structure, the age structure is aging. The incidence of prostate cancer is rising at a rate of 10% per year. Androgen receptor signaling plays a crucial role in the development of prostate cancer. The traditional prostate cancer bill is androgen deprition treatment, including drugs for androgen and surgical castration. Is to inhibit tumor growth by blocking androgen binding to androgen receptors. This is still the main treatment for prostate cancer. Then, traditional anti-androgen therapy does not completely inhibit the progression of prostate cancer. Most prostate cancer patients relapse in a non-hormone-dependent manner after treatment with ADT. In prostate cancer, androgen receptor (ARR) regulates the way cells die in different ways. Therefore, the effects of ADT on the cell death of prostate cancer are different. In this study, we first studied the regulatory role of AR in Entosis. The mechanism is mainly through the Rho/ROCK pathway to promote cell Entosis.This study has improved AR's regulation of prostate cancer cell death. So far, five ways of cell death have been reported in prostate cancer. ADT promotes apoptosis, necrosis and autophagy in prostate cancer cells, but reduces apoptosis and invasive death in prostate cancer cells. The first three are related to the growth of prostate cancer cells. The latter two are related to the invasion of tumor cells. This leads to ADT inhibiting prostate cancer growth but increasing tumor invasiveness, as a complement to AR growth regulation in prostate cancer cells. This further explains the dual role of AR in prostate cancer. On the basis of the above theory, we found that ADT could not inhibit the key enzyme of fatty acid metabolism, FASN and tumor stem / progenitor cells, under castration. This study reveals why ADT is not effective in castration resistant prostate cancer and makes the tumor more aggressive. Further further, this study provides a new anti-prostate cancer drug ASC-J9. One drug has more advantages than traditional ADT (such as Casodex and MDV3100). First, ASC-J9 can inhibit tumor progression through the AR pathway of ASC-J9-AR-SREBP1-FASN, and is more effective than traditional ADT. In ovariectomized prostate cancer (or in prostate tissues with negative AR expression), ASC-J9-PI3K / AKT-SREBP1-FASNs can inhibit tumor progression through non-AR pathway. Finally, ASC-J9 can inhibit tumor progression at a deeper level by inhibiting tumor stem / progenitor cells. ASC-J9 offers a better therapeutic effect on prostate cancer than current ADT drugs. Is a possible option for the next generation of anti-prostate cancer drugs.
【学位授予单位】：天津医科大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R737.25

【共引文献】