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Apoptosis

, 16:1028 | Cite as

Celastrol inhibits tumor cell proliferation and promotes apoptosis through the activation of c-Jun N-terminal kinase and suppression of PI3 K/Akt signaling pathways

  • Radhamani Kannaiyan
  • Kanjoormana Aryan Manu
  • Luxi Chen
  • Feng Li
  • Peramaiyan Rajendran
  • Aruljothi Subramaniam
  • Paula Lam
  • Alan Prem Kumar
  • Gautam Sethi
Original Paper

Abstract

Celastrol, a plant triterpene has attracted great interest recently, especially for its potential anti-inflammatory and anti-cancer activities. In the present report, we investigated the effect of celastrol on proliferation of various cancer cell lines. The mechanism, by which this triterpene exerts its apoptotic effects, was also examined in detail. We found that celastrol inhibited the proliferation of wide variety of human tumor cell types including multiple myeloma, hepatocellular carcinoma, gastric cancer, prostate cancer, renal cell carcinoma, head and neck carcinoma, non-small cell lung carcinoma, melanoma, glioma, and breast cancer with concentrations as low as 1 μM. Growth inhibitory effects of celastrol correlated with a decrease in the levels of cyclin D1 and cyclin E, but concomitant increase in the levels of p21 and p27. The apoptosis induced by celastrol was indicated by the activation of caspase-8, bid cleavage, caspase-9 activation, caspase-3 activation, PARP cleavage and through the down regulation of anti-apoptototic proteins. The apoptotic effects of celastrol were preceded by activation of JNK and down-regulation of Akt activation. JNK was needed for celastrol-induced apoptosis, and inhibition of JNK by pharmacological inhibitor abolished the apoptotic effects. Overall, our results indicate that celastrol can inhibit cell proliferation and induce apoptosis through the activation of JNK, suppression of Akt, and down-regulation of anti-apoptotic protein expression.

Keywords

Celastrol Apoptosis Cancer Akt JNK 

Abbreviations

NF-κB

Nuclear factor-kappa B

FBS

Fetal bovine serum

GSK3β

Glycogen synthase kinase 3 beta

SDS

Sodium dodecyl sulfate

TUNEL

Terminal deoxyuridine triphosphate nick end-labeling

JNK

c-Jun N-terminal kinase

PARP

Poly (ADP-ribose) polymerase

PI3K

Phosphoinositide 3-kinase

PDK1

3-phosphoinositide-dependent protein kinase-1

VEGF

Vascular endothelial growth factor

XIAP

X-linked inhibitor of apoptosis

Notes

Acknowledgments

This work was supported by grants from National Medical Research Council of Singapore (Grant R-184-000-201-275), Academic Research Fund (Grant R-184-000-177-112) and National Kidney Foundation (Grant R-184-000-196-592) to GS. APK was supported by grants from the National Medical Research Council of Singapore (Grant R-713-000-124-213) and Cancer Science Institute of Singapore, Experimental Therapeutics I Program (Grant R-713-001-011-271).

Conflict of interest

None.

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Radhamani Kannaiyan
    • 1
  • Kanjoormana Aryan Manu
    • 1
  • Luxi Chen
    • 2
  • Feng Li
    • 1
  • Peramaiyan Rajendran
    • 1
  • Aruljothi Subramaniam
    • 1
  • Paula Lam
    • 3
  • Alan Prem Kumar
    • 2
  • Gautam Sethi
    • 2
  1. 1.Department of Pharmacology, Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
  2. 2.Department of Pharmacology, Yong Loo Lin School of Medicine, and Cancer Science InstituteNational University of SingaporeSingaporeSingapore
  3. 3.Laboratory of Cancer Gene Therapy, Division of Cellular and Molecular ResearchHumprey Oei Institute of Cancer Research, National Cancer CentreSingaporeSingapore

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