J Cancer 2017; 8(12):2163-2172. doi:10.7150/jca.19940
CENPH Inhibits Rapamycin Sensitivity by Regulating GOLPH3-dependent mTOR Signaling Pathway in Colorectal Cancer
Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, Beijing 100142, China.
# These authors contributed equally to this work.
Background: Centromere protein H (CENPH) is known as a fundamental component of the active centromere complex, and its overexpression is correlated with poor prognosis in various solid tumors. mTOR inhibitor rapamycin has been shown to possess antitumor activity, as well as prevent intestinal tumorigenesis. However, the prognostic value of CENPH in colorectal cancer (CRC) and the role of CENPH in rapamycin sensitivity remain unknown.
Materials and methods: The effect of CENPH on the cell proliferation, clonogenicity, and cell response to rapamycin in CRC were evaluated by MTT and/or colony formation assays. For the underlying mechanisms, the interaction between CENPH and GOLPH3 were detected by co-immunoprecipitation, GST pull-down, and His-tag pull-down assays, as well as the laser scanning confocal microscopy. The status of kinases in mTOR signaling was determined by Western blot. Finally, the clinical significance of CENPH was analyzed using public CRC datasets with CENPH transcripts and clinical information.
Results: CENPH inhibited CRC malignant phenotypes, conferred reduced sensitivity to rapamycin, and attenuated both mTORC1 and mTORC2 in mTOR signaling pathway through the interaction with golgi phosphoprotein 3 (GOLPH3), which has been identified as a potential oncogene and modulates the response to rapamycin. Moreover, elevated levels of CENPH were detected in CRC tissues, compared with normal colorectal tissues. High levels of CENPH expression gradually decreased according to CRC tumor stages. Patients with high CENPH expression had favorable survival.
Conclusions: Our results suggest that CENPH inhibits rapamycin sensitivity by regulating GOLPH3 dependent mTOR pathway. High CENPH expression is associated with better prognosis in CRC patients. Taken together, CENPH may serve as a potential predictor for rapamycin sensitivity and therapeutic target for CRC patients.
Keywords: CENPH, GOLPH3, Colorectal cancer (CRC), Rapamycin, mTOR, Prognosis.
Wu W, Wu F, Wang Z, Di J, Yang J, Gao P, Jiang B, Su X. CENPH Inhibits Rapamycin Sensitivity by Regulating GOLPH3-dependent mTOR Signaling Pathway in Colorectal Cancer. J Cancer 2017; 8(12):2163-2172. doi:10.7150/jca.19940. Available from http://www.jcancer.org/v08p2163.htm