Abstract
Epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I) are critical regulators of cell differentiation, survival, proliferation, and migration in cancers. This study found that ARNO (cytohesin-2), an activator of the EGF and IGF-I pathways, was more highly expressed in colorectal cancer tissue than in benign adjacent colorectal tissue. When ARNO-siRNA or the chemical inhibitor SecinH3 blocked ARNO, the downstream of the EGF and IGF-I pathways decreased in colorectal cell lines HT29 and HCT116. This blocking also weakened cell proliferation, invasion, and migration in vitro. Furthermore, EGF receptor (EGFR)-dependent colorectal tumor xenografts in nude mouse exerted anti-proliferative and growth suppression effects by injecting secineH3. These data suggested that inhibiting cytohesins or ARNO as cytoplasmic activators of EGFR and IGF-I in colorectal cancer resulted in anti-proliferation, reduced invasion, decreased migration, and suppressed growth in vivo and in vitro. Therefore, cytohesins or ARNO may be a potential therapy target for some colorectal cancer.
Highlights
Colorectal cancer (CRC) remains to be the third most commonly diagnosed cancer in males and the second in females despite significant improvements in its prognosis ascribed to advances in diagnosis and therapy modalities
We wondered whether ARNO was over expressed in patients’ cancer tissues and the over expression was correlated with EGF receptor (EGFR) and insulinlike growth factor (IGF)-IR signaling
Our previous study has shown that ARNO is the most important cytohesin and is over expressed in colorectal cancer cell lines as an activator that plays a crucial role in EGFR pathway signaling [17]
Summary
Colorectal cancer (CRC) remains to be the third most commonly diagnosed cancer in males and the second in females despite significant improvements in its prognosis ascribed to advances in diagnosis and therapy modalities. Over 1.2 million new cancer cases and 608 700 deaths are recorded annually [1]. The effective treatments of colorectal cancer are surgery, chemotherapy, and targeted therapy. Advances in conventional chemotherapy have extended life expectancy, but the effectiveness for many patients remains low, especially for those with metastasis. The search for more effective and less toxic therapies has given rise to a new generation of antitumor agents. Epidermal growth factor (EGF) receptor (EGFR) and associated signal transduction pathways have emerged as important molecular therapeutic targets for colorectal cancer [3]
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