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Ursolic acid inhibits multiple cell survival pathways leading to suppression of growth of prostate cancer xenograft in nude mice

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Abstract

Activation of transcription factors nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) is frequently observed in prostate cancer and has been linked with tumor cell proliferation, invasion, metastasis, and angiogenesis. In this study, we investigated the effect of ursolic acid (UA) on NF-κB and STAT3 signaling pathways in both androgen-independent (DU145) and androgen-dependent (LNCaP) prostate cancer cell lines and also prospectively tested the hypothesis of NF-κB and STAT3 inhibition using a virtual predictive functional proteomics tumor pathway technology platform. We found that UA inhibited constitutive and TNF-α-induced activation of NF-κB in DU145 and LNCaP cells in a dose-dependent manner. The suppression was mediated through the inhibition of constitutive and TNF-α-induced IκB kinase (IKK) activation, phosphorylation of IκBα and p65 and NF-κB-dependent reporter activity. Furthermore, UA suppressed both constitutive and inducible STAT3 activation in prostate cancer cells concomitant with suppression of activation of upstream kinases (Src and JAK2) and STAT3-dependent reporter gene activity. UA also downregulated the expression of various NF-κB and STAT3 regulated gene products involved in proliferation, survival, and angiogenesis and induced apoptosis in both cells lines as evidenced by DNA fragmentation and annexin V staining. In vivo, UA (200 mg/kg b.w.) treated for 6 weeks inhibited the growth of DU145 cells in nude mice without any significant effect on body weight. Overall, our results from experimental and predictive studies suggest that UA mediates its anti-tumor effects through suppression of NF-κB and STAT3 pathways in prostate cancer.

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Acknowledgments

This work was supported by grants from National Medical Research Council of Singapore (Grant R-184-000-168-275, Grant R-184-000-157-214) 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). KMH was supported by grant from the National Medical Research Council of Singapore, Biomedical Research Council of Singapore, and the Singapore Millennium Foundation.

Conflict of interests

No potential conflict of interest is declared.

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Authors and Affiliations

  1. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore

    Muthu K. Shanmugam, Peramaiyan Rajendran, Feng Li, Alan Prem Kumar & Gautam Sethi

  2. Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore

    Tarang Nema & Paul C. Ho

  3. Cellworks Group Inc., Saratoga, CA, 95070, USA

    Shireen Vali, Taher Abbasi, Shweta Kapoor & Ashish Sharma

  4. Cellworks Research India Pvt. Ltd, Bangalore, 560066, India

    Shireen Vali, Taher Abbasi, Shweta Kapoor & Ashish Sharma

  5. Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117456, Singapore

    Alan Prem Kumar

  6. Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore, 169610, Singapore

    Kam M. Hui

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  1. Muthu K. Shanmugam
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  2. Peramaiyan Rajendran
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Correspondence to Gautam Sethi.

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Shanmugam, M.K., Rajendran, P., Li, F. et al. Ursolic acid inhibits multiple cell survival pathways leading to suppression of growth of prostate cancer xenograft in nude mice. J Mol Med 89, 713–727 (2011). https://doi.org/10.1007/s00109-011-0746-2

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  • DOI: https://doi.org/10.1007/s00109-011-0746-2

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