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Berberine modifies cysteine 179 of IkappaBalpha kinase, suppresses nuclear factor-kappaB-regulated antiapoptotic gene products, and potentiates apoptosis.
Cancer Res. 2008 Jul 01; 68(13):5370-9.CR

Abstract

Berberine, an isoquinoline alkaloid derived from a plant used traditionally in Chinese and Ayurvedic medicine, has been reported to exhibit chemopreventive and anti-inflammatory activities through unknown mechanism. Because of the critical role of the transcription factor nuclear factor-kappaB (NF-kappaB) in these processes, we investigated the effect of berberine on this pathway. We found that berberine suppressed NF-kappaB activation induced by various inflammatory agents and carcinogens. This alkaloid also suppressed constitutive NF-kappaB activation found in certain tumor cells. Suppression of NF-kappaB activation occurred through the inhibition of phosphorylation and degradation of IkappaBalpha by the inhibition of IkappaB kinase (IKK) activation, leading to suppression of phosphorylation and nuclear translocation of p65, and finally to inhibition of NF-kappaB reporter activity. Inhibition of IKK by berbeine was direct and could be reversed by reducing agents. Site-specific mutagenesis suggested the involvement of cysteine residue 179 in IKK. Berberine also suppressed the expression of NF-kappaB-regulated gene products involved in antiapoptosis (Bcl-xL, Survivin, IAP1, IAP2, and cFLIP), proliferation (cyclin D1), inflammation (cyclooxygenase-2), and invasion (matrix metalloproteinase-9). Suppression of antiapoptotic gene products correlated with enhancement of apoptosis induced by tumor necrosis factor (TNF)-alpha and chemotherapeutic agents and with inhibition of TNF-induced cellular invasion. Overall, our results indicate that chemopreventive, apoptotic, and anti-inflammatory activities displayed by berberine may be mediated in part through the suppression of the NF-kappaB activation pathway. This may provide the molecular basis for the ability of berberine to act as an anticancer and anti-inflammatory agent.

Authors+Show Affiliations

Department of Experimental Therapeutics, Cytokine Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

18593939

Citation

Pandey, Manoj K., et al. "Berberine Modifies Cysteine 179 of IkappaBalpha Kinase, Suppresses Nuclear factor-kappaB-regulated Antiapoptotic Gene Products, and Potentiates Apoptosis." Cancer Research, vol. 68, no. 13, 2008, pp. 5370-9.
Pandey MK, Sung B, Kunnumakkara AB, et al. Berberine modifies cysteine 179 of IkappaBalpha kinase, suppresses nuclear factor-kappaB-regulated antiapoptotic gene products, and potentiates apoptosis. Cancer Res. 2008;68(13):5370-9.
Pandey, M. K., Sung, B., Kunnumakkara, A. B., Sethi, G., Chaturvedi, M. M., & Aggarwal, B. B. (2008). Berberine modifies cysteine 179 of IkappaBalpha kinase, suppresses nuclear factor-kappaB-regulated antiapoptotic gene products, and potentiates apoptosis. Cancer Research, 68(13), 5370-9. https://doi.org/10.1158/0008-5472.CAN-08-0511
Pandey MK, et al. Berberine Modifies Cysteine 179 of IkappaBalpha Kinase, Suppresses Nuclear factor-kappaB-regulated Antiapoptotic Gene Products, and Potentiates Apoptosis. Cancer Res. 2008 Jul 1;68(13):5370-9. PubMed PMID: 18593939.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Berberine modifies cysteine 179 of IkappaBalpha kinase, suppresses nuclear factor-kappaB-regulated antiapoptotic gene products, and potentiates apoptosis. AU - Pandey,Manoj K, AU - Sung,Bokyung, AU - Kunnumakkara,Ajaikumar B, AU - Sethi,Gautam, AU - Chaturvedi,Madan M, AU - Aggarwal,Bharat B, PY - 2008/7/3/pubmed PY - 2008/8/6/medline PY - 2008/7/3/entrez SP - 5370 EP - 9 JF - Cancer research JO - Cancer Res VL - 68 IS - 13 N2 - Berberine, an isoquinoline alkaloid derived from a plant used traditionally in Chinese and Ayurvedic medicine, has been reported to exhibit chemopreventive and anti-inflammatory activities through unknown mechanism. Because of the critical role of the transcription factor nuclear factor-kappaB (NF-kappaB) in these processes, we investigated the effect of berberine on this pathway. We found that berberine suppressed NF-kappaB activation induced by various inflammatory agents and carcinogens. This alkaloid also suppressed constitutive NF-kappaB activation found in certain tumor cells. Suppression of NF-kappaB activation occurred through the inhibition of phosphorylation and degradation of IkappaBalpha by the inhibition of IkappaB kinase (IKK) activation, leading to suppression of phosphorylation and nuclear translocation of p65, and finally to inhibition of NF-kappaB reporter activity. Inhibition of IKK by berbeine was direct and could be reversed by reducing agents. Site-specific mutagenesis suggested the involvement of cysteine residue 179 in IKK. Berberine also suppressed the expression of NF-kappaB-regulated gene products involved in antiapoptosis (Bcl-xL, Survivin, IAP1, IAP2, and cFLIP), proliferation (cyclin D1), inflammation (cyclooxygenase-2), and invasion (matrix metalloproteinase-9). Suppression of antiapoptotic gene products correlated with enhancement of apoptosis induced by tumor necrosis factor (TNF)-alpha and chemotherapeutic agents and with inhibition of TNF-induced cellular invasion. Overall, our results indicate that chemopreventive, apoptotic, and anti-inflammatory activities displayed by berberine may be mediated in part through the suppression of the NF-kappaB activation pathway. This may provide the molecular basis for the ability of berberine to act as an anticancer and anti-inflammatory agent. SN - 1538-7445 UR - https://www.unboundmedicine.com/medline/citation/18593939/Berberine_modifies_cysteine_179_of_IkappaBalpha_kinase_suppresses_nuclear_factor_kappaB_regulated_antiapoptotic_gene_products_and_potentiates_apoptosis_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=18593939 DB - PRIME DP - Unbound Medicine ER -