Release of overexpressed CypB activates ERK signaling through CD147 binding for hepatoma cell resistance to oxidative stress
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Cyclophilin, a cytosolic receptor for the immunosuppressive drug cyclosporin A, plays a role in diverse pathophysiologies along with its receptor, CD147. Although the interaction between cyclophilin A and CD147 is well established in inflammatory disease, that of cyclophilin B (CypB) with CD147 has not been fully explored, especially in cancer cell biology, and the exact molecular mechanism underlying such an association is poorly understood. In this study, we first identified high expression levels of CypB in 54 % of hepatocellular carcinoma patient tissues but in only 12.5 % of normal liver tissues. Then, we demonstrated that CypB overexpression protects human hepatoma cells against oxidative stress through its binding to CD147; this protective effect depends on the peptidyl prolyl isomerase activity of CypB. siRNA-mediated knockdown of CypB expression rendered hepatoma cells more vulnerable to ROS-mediated apoptosis. Furthermore, we also determined that a direct interaction between secreted CypB and CD147 regulates the extracellular signal-regulated kinase intracellular signaling pathway and is indispensible for the protective functions of CypB. For the first time, we demonstrated that CypB has an essential function in protecting hepatoma cells against oxidative stress through binding to CD147 and regulating the ERK pathway.
KeywordsCyclophilin B ROS Hepatoma cells CD147 ERK signaling PPIase activity Cyclosporin A
This study was supported by the Basic Science Program through the National Research Foundation of Korea funded by the Ministry of Education, Science, and Technology (Grants 2009–0072431 and 20090063274) and by a grant from the Next-Generation BioGreen 21 Program (No. PJ008086), Rural Development Administration, Republic of Korea, and a grant of the Korean Heath Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A092125).
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