Department of Urology, Yale University, New Haven, CT, USA.
Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Cell Signal. 2019 Nov;63:109381. doi: 10.1016/j.cellsig.2019.109381. Epub 2019 Jul 30.
Multidrug resistance is a major treatment obstacle for recurrent and metastatic bladder cancer, which often leads to disease progression and poor clinical outcome. Although overexpression of interleukin-6 (IL-6) appears to play a critical role in the development of chemotherapy resistance, inhibitors for IL-6 alone have not improved clinical outcomes. Since the IL-6/IL-6R/GP130 complex is involved in multidrug resistance, another strategy would be to focus on glycoprotein-130 (GP130) since it dimerizes with IL-6R/CD26 as a membrane-bound signaling transducer receptor and initiates subsequent signaling activation and may be a potential therapeutic target. Currently, the role of GP130 in chemoresistant bladder cancer is unknown. In the present study, we demonstrate that GP130 is over-expressed in cisplatin and gemcitabine-resistant bladder cancer cells, and that the inhibition of GP130 expression significantly reduces cell viability, survival and migration. Downstream of GP130 is PI3K/AKT/mTOR signaling, which is inactivated by SC144, a GP130 inhibitor. However, Raf/MEK/ERK signaling, which also is downstream of GP130 is activated by SC144. This activation is likely based on a mTOR/S6K1/PI3K/ERK negative feedback loop, which is presumed to counteract the inhibitory effect of SC144 on tumor aggressiveness. Blocking both GP130 and pERK resulted in synergistic inhibition of cytotoxicity, clonal survival rates and cell migration in our chemotherapy resistant bladder cancer cells. This vertical inhibition offers a novel therapeutic strategy for targeting human chemoresistant bladder cancer.
多药耐药是复发性和转移性膀胱癌的主要治疗障碍，这通常导致疾病进展和不良的临床结果。尽管白细胞介素-6（IL-6）的过度表达似乎在化疗耐药的发展中起关键作用，但单独使用 IL-6 的抑制剂并未改善临床结果。由于 IL-6/IL-6R/GP130 复合物参与多药耐药，另一种策略是专注于糖蛋白-130（GP130），因为它与 IL-6R/CD26 二聚化作为膜结合信号转导受体，并启动随后的信号激活，并且可能是一个潜在的治疗靶点。目前，GP130 在耐药性膀胱癌中的作用尚不清楚。在本研究中，我们证明 GP130 在顺铂和吉西他滨耐药的膀胱癌细胞中过度表达，并且抑制 GP130 表达显著降低细胞活力、存活和迁移。GP130 的下游是 PI3K/AKT/mTOR 信号通路，GP130 抑制剂 SC144 使其失活。然而，GP130 的下游 Raf/MEK/ERK 信号也被 SC144 激活。这种激活可能基于 mTOR/S6K1/PI3K/ERK 负反馈回路，该回路被认为可以抵消 SC144 对肿瘤侵袭性的抑制作用。在我们的化疗耐药膀胱癌细胞中，同时阻断 GP130 和 pERK 导致细胞毒性、克隆存活率和细胞迁移的协同抑制。这种垂直抑制为靶向人类化疗耐药性膀胱癌提供了一种新的治疗策略。
