Research Express@NCKU - Articles Digest
Research Express@NCKU Volume 9 Issue 6 - July 3, 2009 [ http://research.ncku.edu.tw/re/articles/e/20090703/1.html ]
Eps8 is a potential anticancer drug target in
colorectal cancer
Tzeng-Horng Leu
Department of Pharmacology, College of Medicine, National Cheng Kung University tzengleu@mail.ncku.edu.tw
M.-C. Maa, J.-C. Lee, Y.-J. Chen, Y.-J Chen, Y.-C. Lee, S.-T. Wang, C.-C. Huang, N.-H.
Chow, and T.-H. Leu (2007) Eps8 facilitates cellular growth and motility of colon cancer cells by increasing the expression and activity of focal adhesion kinase. J.
Biol. Chem. 282,19399-19409
E
ps8 (EGF receptor pathway substrate number 8) is an adaptor protein and a common substrate for both EGF receptor and Src tyrosine kinase. Src not only can phosphorylate Eps8 but also influence its expression. Overexpression of Eps8 in murine fibroblasts led to cellular transformation, and remarkably, upregulation of Eps8 played a pivotal role in Src-mediated carcinogenesis. Of note, Eps8 is also an actin capper that can regulate Rac activation and actin-based mobility.Colorectal cancer (CRC) is one of the ten leading cancers and one of the major causes of cancer mortality regardless of sex difference worldwide. Elevated expression and/or activity of Src and its substrate, focal adhesion kinase (FAK), are reported to associate with the progression of colorectal adenoma to invasive carcinoma. Despite the role of Eps8 in mitogenesis and migration is well established, its contribution to human neoplasm is still unclear. To address this issue, plasmids expressing nonspecific siRNA or eps8- specific siRNA were introduced into SW620 and WiDr cells to obtain the corresponding control and Eps8-attenuated cells. Eps8 diminishment resulted in reduced proliferation, colony formation in soft agar and promotion of xenografting tumor growth in colon cancer cells. Interestingly, reintroduction of Eps8 rescued these defects. Eps8 attenuation decreased Src Pi-Tyr-416, Shc-Pi-Tyr-317, and serum- evoked FAK Pi-Tyr-397 and Pi-Tyr-861. Astonishingly, Eps8 could increase the expression of FAK by mTOR/STAT3 Pi-Ser-727. Due to forced expression of FAK in Eps8 knockdown cells restored cellular growth and mobility, we concluded that Eps8-induced proliferation and locomotion was partly
attributable to FAK.
Consistent with the importance of Eps8 in both cell proliferation and motility in colonocytes,
preferentially augmented Eps8 in the advanced stage of human CRC was observed. In agreement with Eps8-elicited FAK expression, the concomitant enhancement of FAK and Eps8 was detected in tumor specimen. Since Src can increase the expression of Eps8, which in turn could up-regulate FAK, a previously unidentified hierarchy of mutual regulation among Eps8, Src, and FAK contribution to the formation of human CRC could be postulated in Figure 1. In this model, Eps8 overexpression augments not only the expression of FAK and cyclin D1 via mTOR/STAT3 pathway but also promotes activation of Src and FAK. Meanwhile, Src retains the ability to enhance Eps8 expression, which in turn further provokes the expression and activity of FAK required for colonocyte proliferation and migration. These events accelerate disease progression of colon cancer. Given all these evidences, the involvement of
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Research Express@NCKU - Articles Digest
Eps8 in colon tumor formation and progression is confirmed. Since downregulation of Eps8 reduces mitogenesis and mobility of colon cancer cells, searching for agents with Eps8 attenuation activity might open a totally novel avenue for colon cancer treatment.
Figure 1. Model of Eps8, Src, and FAK in the progression of colon cancer (adapted from J.
Bio. Chem. 282, 19399-19409, 2007).
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