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A novel CXCR4‐ARF1‐MAPK signaling pathway controls prostate tumorigenesis
Author(s) -
Davis Jason E,
Wu William H,
Surrao Kristen,
Teng Yong,
Wu Guangyu
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.714.3
Subject(s) - prostate cancer , mapk/erk pathway , cancer research , carcinogenesis , cxcr4 , prostate , cancer , cell growth , biology , signal transduction , chemistry , medicine , microbiology and biotechnology , chemokine , receptor , biochemistry
Prostate cancer is one of the most common cancers in men and is the second leading cause of cancer‐related mortality in men. It is well known that enhanced activation of the MAPK pathway Raf‐MEK‐ERK1/2 directly correlates with the progression, androgen independence and poor prognosis of prostate cancer. Recent studies have also shown that the chemokine receptor CXCR4 is highly expressed in prostate cancer and contributes to prostate tumor growth and metastasis. However, the molecular mechanisms underlying the hyper‐activation of MAPK and the function of CXCR4 remain poorly elucidated. Here, we demonstrated that CXCL12‐induced CXCR4 activation markedly enhanced the activation of ADP‐ribosylation factor 1 (ARF1), a Ras‐related small G protein, in a time‐ and concentration‐dependent fashion, and siRNA‐mediated depletion of ARF1 dramatically inhibited MAPK activation by CXCR4 in prostate cancer cells. More interestingly, we found that ARF1 can mimic Ras to directly and activation‐dependently interact with Raf1, specifically its Ras‐binding domain. Mutations that disrupted ARF1 activation considerably attenuated ARF1‐Raf1 interaction and MAPK activation. These data suggest that, through its direct interaction with Raf1, ARF1 regulates the MAPK activation by CXCR4 in prostate cancer cells. We then investigated the role of ARF1 in prostate tumorigenesis. We found that ARF1 expression and activation were markedly elevated in human prostate cancer cells and tissues. Depletion of ARF1 significantly inhibited prostate cancer cell proliferation in vitro and xenograft tumor growth in vivo , whereas over‐expression of ARF1 produced opposing effects. These data have revealed an unappreciated function of ARF1 in prostate cancer. Altogether, our studies have identified a novel CXCR4‐ARF1‐MAPK signaling pathway which plays an important role in prostate tumorigenesis and may represent a key molecular target for therapeutic innovation (R01GM076167). Support or Funding Information R01GM076167