ARHGAP17 enhances 5-Fluorouracil-induced apoptosis in colon cancer cells by suppressing Rac1

Abstract

Colon cancer is a common cause of death in the world, and its main cause of therapy failure is chemoresistance. Apoptosis is de-regulated in colon cancer and is one key mechanism of cancer treatment. We recently reported that reduced expression of ARHGAP17, a Rho GTPase activating protein, correlated with a poor prognosis of colon cancer patients. Here we investigated the role of ARHGAP17 in apoptosis induced by 5-Fluorouracil (5-FU) in human colon cancer cells and in mouse xenograft tumor model. We observed a decreased protein level o f ARHGAP17 in 5-FU resistant colon cancer cells (HCT116/5-FU and HCT8/5-FU). While ARHGAP17 knockdown attenuated apoptosis upon 5-FU treatment in HCT116 and HCT8, and ARHGAP17 overexpression in HCT116/5-FU and HCT8/5-FU cells increased apoptosis induced by 5-FU. We also found that ARHGAP17 knockdown led to a high level of active Rac1 in HCT116 and HCT8, but ARHGAP17 overexpression reduced active Rac1 in HCT116/5-FU and HCT8/5-FU cells. However, Rac1 inhibitor abolished the effect of ARHGAP17 knockdown, and Rac1 overexpression diminished the effect of ARHGAP17 overexpression on apoptosis induced by 5-FU. Apoptosis was also confirmed by cleaved Caspase-3 and cleaved PARP. Further, we observed that overexpression of ARHGAP17 promoted 5-FU-induced apoptosis and attenuated tumor growth in vivo. Collectively, our data indicate that ARHGAP17 sensitizes chemotherapy-resistant colon cancer cells to apoptosis induced by 5-FU, which is in part through suppressing Rac1.

ARHGAP17 regulates the spatiotemporal activity of Cdc42 at invadopodia

“…Our report is the first to describe ARHGAP17 at invadopodia and a direct mechanism regarding the link between ARHGAP17 and cancer cell invasion. ARHGAP17 has been previously characterized as a tumor suppressor and found to be downregulated in a variety of cancers, including colon, breast, and cervical, where it functions to inhibit migration and invasion ( Guo et al, 2019 ; Kiso et al, 2018 ; Pan et al, 2018 ; Pan et al, 2022 ; Tian et al, 2022 ). ARHGAP17 is downregulated by VEGF/NRP1 signaling in TNBC which was associated with increased Cdc42 activity, filopodia formation, and cell migration ( Kiso et al, 2018 ).…”

RICH1 is a novel key suppressor of isoproterenol‑ or angiotensin II‑induced cardiomyocyte hypertrophy

“…The GAP activity of RICH1 and regulation of Cdc42 by RICH1 is required for maintaining proper tight junctions in epithelial cells ( 21 ). RICH1 is widely distributed and highly expressed in human heart and placenta tissues ( 23 ), and it has been reported that RICH1 has multiple functions in vivo ( 24 – 26 ). RICH1 can inhibit the activity of Rac1 by catalyzing the cleavage of Rac1-GTP to Rac1-GDP, which then inhibits the MAPK signaling pathway, which in turn reduces cellular proliferation and tumorigenesis ( 27 , 28 ).…”