ARF1 promotes prostate tumorigenesis via targeting oncogenic MAPK signaling

Abstract

ADP-ribosylation factor 1 (ARF1) is a crucial regulator in vesicle-mediated membrane trafficking and involved in the activation of signaling molecules. However, virtually nothing is known about its function in prostate cancer. Here we have demonstrated that ARF1 expression is significantly elevated in prostate cancer cells and human tissues and that the expression levels of ARF1 correlate with the activation of mitogen-activated protein kinases (MAPK) ERK1/2. Furthermore, we have shown that overexpression and knockdown of ARF1 produce opposing effects on prostate cancer cell proliferation, anchorage-independent growth and tumor growth in mouse xenograft models and that ARF1-mediated cell proliferation can be abolished by the Raf1 inhibitor GW5074 and the MEK inhibitors U0126 and PD98059. Moreover, inhibition of ARF1 activation achieved by mutating Thr48 abolishes ARF1′s abilities to activate the ERK1/2 and to promote cell proliferation. These data demonstrate that the aberrant MAPK signaling in prostate cancer is, at least in part, under the control of ARF1 and that, similar to Ras, ARF1 is a critical regulator in prostate cancer progression. These data also suggest that ARF1 may represent a key molecular target for prostate cancer therapeutics and diagnosis.

Targeting the Ras/Raf/MEK/ERK pathway in hepatocellular carcinoma

“…U0126 is widely used in in vitro experiments (60). In HepG2 cell cultures in vitro, the phosphorylation of p38 and ERK1/2 was inhibited by PD98059, and this effect was also demonstrated in vivo (61). The two types of MEK1/2 kinase inhibitors are non-ATP-competitive, acting by inhibiting the MEK excitation instead of directly inhibiting the activity of MEK.…”

The Role of ARF Family Proteins and Their Regulators and Effectors in Cancer Progression: A Therapeutic Perspective

“…ARF1 plays a central role in maintaining the structure and function of the Golgi apparatus and is highly expressed in breast, prostate and ovarian cancers (Schlienger et al, 2015;Davis et al, 2016;Gu et al, 2017). In the context of cancer, ARF1 has an important function in inter-and intracellular signaling, cell cycle regulation and DNA repair, as well as necrosis and apoptosis (D'Souza-Schorey and Chavrier, 2006;Gu et al, 2017).…”

“…Furthermore, ARF1 sensitizes MDA-MB-231 breast cancer cells to the anti-tumor drugs actinomycin D and vinblastine through ERK and Akt signaling (Luchsinger et al, 2018). In prostate cancer, ARF1 promotes tumorigenesis by controlling MAPK activation and cell growth (Davis et al, 2016). In myeloma cells, ARF1 expression promotes cell proliferation and inhibits cell adhesion, controlling proliferation-and cell adhesion-mediated drug resistance (Xu et al, 2017).…”

“…Moreover, ARF3 overexpression promotes breast cancer cell proliferation by regulating the cellcycle G1/S transition, through inhibition of FOXO1 transcription factor activity . Additionally, ARF3 was found to be a candidate gene involved in the progression of Olstad et al, 2003;Ma et al, 2005;Kannangai et al, 2007;Tsai et al, 2012;Schlienger et al, 2015;Davis et al, 2016;Gu et al, Woo et al, 2009;Bidkhori et al, 2013;Howley et al, 2018;Wu Q. et al, 2018ARF6 ↑ Breast, Gastric, Glioma, Liver, Lung, Melanoma, Pancreatic, Prostate, Renal Cell Carcinoma Hashimoto et al, 2004Hu et al, 2009;Knizhnik et al, 2011;Oka et al, 2014;Morgan et al, 2015;Zhang et al, 2015;Hashimoto et al, 2016;Liang et al, 2017; Fujii et al, 2014;Guo et al, 2015;Fujii et al, 2016;Hu et al, 2018;Chen et al, 2019;Harada et al, 2019;Isono et al, Calin et al, 2005;Petrocca et al, 2006;Yendamuri et al, 2008;Siltanen et al, pregnancy-associated breast cancer, based on integrated analysis of microarray profile datasets (Zhang et al, 2019).…”

Proteogenomics of Colorectal Cancer Liver Metastases: Complementing Precision Oncology with Phenotypic Data

“…The ADP-ribosylation factor 1 (ARF1) has been reported as significantly elevated in various cancers [41], and its expression in prostate cancer correlated with activation of ERK1 and ERK2, leading to cell proliferation [42]. We found ARF1 to be significantly higher in the WT tumor proteome (ARF1↑WT; no peptides/PSM in G12V vs. 10 peptides and 137 PSM in WT), which might represent an EGFR-independent activation of the RAS/MEK/ERK pathway and a potential escape mechanism for anti-EGFR therapy.…”