Synergistic inhibition of GP130 and ERK signaling blocks chemoresistant bladder cancer cell growth

Cellular Signalling
Xuanhao LiDarryl T Martin

Abstract

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 p...Continue Reading

Citations

Jun 11, 2020·Journal of Cellular Physiology·Milad AshrafizadehSaeed Samarghandian
Aug 8, 2020·International Journal of Molecular Sciences·Saira JustinRoman A Blaheta
Feb 20, 2021·Journal of Controlled Release : Official Journal of the Controlled Release Society·Gang LiIjeoma F Uchegbu

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