探討Slit1蛋白在抗去勢型攝護腺癌進展過程中所扮演之角色

Abstract

雄性賀爾蒙去除療法(androgen deprivation therapy)是轉移型攝護腺癌的標準療法，然而腫瘤在給予雄性賀爾蒙去除療法的數年後便復發並轉變成高死亡率的抗去勢型攝護腺癌(castration resistant prostate cancer, CRPC)。然而其機制目前尚未了解，因此本研究利用Bicalutamide來建立一雄性賀爾蒙受體與攝護腺特異抗原低表現(ARlow/PSAlow)之抗去勢型攝護腺癌細胞株，LN30，並進一步發現一軸突導向(axon guidance)分子，Slit1在LN30細胞中有大量表現的現象。在臨床資料庫中發現腫瘤細胞中Slit1的高表現與無疾病存活期(disease free survival)有一負相關之現象。Slit1可以作為AR的輔活化因子(coactivator)，直接與AR交互作用並促進AR的活性，導致攝護腺癌細胞可以存活於雄性賀爾蒙去除療法並對其產生抗性。LN30不論在體外模式或體內模式體外模式中，細胞去除Slit1後其細胞生長受到顯著性的抑制。此外，我們更發現Slit1不僅在攝護腺癌中扮演重要的角色，也在內皮細胞中有有ㄧ重要的角色。Slit1為一分泌型分子，在體外試驗模式中Slit1可透過旁分泌(paracrine)的機制誘導人類臍帶靜脈內皮細胞(human, umbilical vein endothelial cells, HUVECs)增生、移行與管狀構造形成，在體內試驗模式中可以促使雞胚胎絨毛尿囊膜(chick chorioallantoic membrane, CAM)的血管數目增加。綜合以上結果，本研究確認Slit1為AR的輔活化因子，且在抗去勢型攝護腺癌中為一有潛力的治療標的。

Androgen deprivation therapy (ADT) is the standard first line therapy for metastatic prostate cancer. Unfortunately, cancer usually relapses after ADT in several years and becomes castration resistant prostate cancer (CRPC) with high mortality. However, the detail mechanism is still unclear. In this study, we use Bicalutamide to establish a CRPC cell line, LN30, with ARlow/PSAlow characteristic. Moreover, we find Slit1, an axon guidance molecule, is overexpression in LN30 cells. Higher Slit1 expression is observed in tumor and inversely correlates with disease free survival in clinical database. Slit1 acts as a coactivator of AR, directly interacts with AR and enhances AR activity to lead prostate cancer cells survive and resistant to ADT. Slit1 depletion dramatically suppressed the growth of LN30 cells in vitro and in vivo model. Moreover, we reveal Slit1 not merely play a pivotal role in prostate cancer cells but also in endothelial cells. Slit1 acts as a paracrine induces proliferation, migration and tube formation in human umbilical vein endothelial cells (HUVECs) in in vitro model and increase blood vessel numbers in CAM assay in in vivo model. Taken together, this study identifies Slit1 as a novel coactivator of AR and a potential therapeutic target in CRPC.