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Apoptosis

, Volume 17, Issue 8, pp 784–796 | Cite as

Release of overexpressed CypB activates ERK signaling through CD147 binding for hepatoma cell resistance to oxidative stress

  • Kiyoon Kim
  • Hunsung Kim
  • Kwon Jeong
  • Min Hyung Jung
  • Bum-Soo Hahn
  • Kyung-Sik Yoon
  • Byung Kwan Jin
  • Geon-Ho Jahng
  • Insug Kang
  • Joohun Ha
  • Wonchae Choe
Original Paper

Abstract

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.

Keywords

Cyclophilin B ROS Hepatoma cells CD147 ERK signaling PPIase activity Cyclosporin A 

Notes

Acknowledgments

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).

Supplementary material

10495_2012_730_MOESM1_ESM.tif (1.3 mb)
Supplemental Fig. 1. a) Chang liver cells and Huh-7 cells were treated with 0, 0.4, 0.6 or 0.8 mM H2O2 for 24 h. After incubation, cell viability was measured by MTT assay. b) Chang cells were treated with 0, 0.4, 0.6 or 0.8 mM H2O2 for 24 h, and CypB mRNA levels were analyzed by real-time RT-PCR. c) Chang cells were transfected with a Mock, CypB/WT or CypB/R95A expression construct and treated with 0, 0.4, 0.6 or 0.8 mM H2O2 for 24 h. After incubation, cell viability was measured by MTT assay. Transfected cells were treated with 0.6 mM H2O2. After 24 h of incubation, cells were harvested, and apoptotic cells were detected with d) Annexin V/PI double staining and e) PI staining. Data are expressed as mean ± SD of three independent experiments. *, P<0.05 vs. Chang cells treated with H2O2; **, P<0.01 vs. Chang cells treated with H2O2; #, P<0.05 vs. mock-transfected cells treated with H2O2; ##, P<0.01 vs. mock-transfected cells treated with H2O2 (TIFF 1363 kb)

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Kiyoon Kim
    • 1
  • Hunsung Kim
    • 1
  • Kwon Jeong
    • 1
  • Min Hyung Jung
    • 2
  • Bum-Soo Hahn
    • 3
    • 4
  • Kyung-Sik Yoon
    • 1
  • Byung Kwan Jin
    • 5
  • Geon-Ho Jahng
    • 6
  • Insug Kang
    • 1
  • Joohun Ha
    • 1
  • Wonchae Choe
    • 1
  1. 1.Department of Biochemistry and Molecular Biology, Medical Science and Engineering Research Center for Bioreaction to Reactive Oxygen Species, Biomedical Science Institute, School of MedicineKyung Hee UniversitySeoulKorea
  2. 2.Department of Obstetrics and Gynecology, School of MedicineKyung Hee UniversitySeoulKorea
  3. 3.National Academy of Agricultural ScienceSuwonKorea
  4. 4.Department of Genetic EngineeringKyung Hee UniversitySuwonKorea
  5. 5.Department of Biochemistry and Molecular Biology, Neurodegeneration Control Research Center, School of MedicineKyung Hee UniversitySeoulKorea
  6. 6.Department of Radiology, Kyung Hee University Hospital-Gangdong, School of MedicineKyung Hee UniversitySeoulKorea

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