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Activation of the RAF/mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase pathway mediates apoptosis induced by chelerythrine in osteosarcoma.
Clin Cancer Res. 2008 Oct 15; 14(20):6396-404.CC

Abstract

PURPOSE

Chelerythrine, a widely used broad-range protein kinase C inhibitor, induces apoptosis in many cell types. In this study, the mechanism of chelerythrine-induced apoptosis in osteosarcoma was investigated.

EXPERIMENTAL DESIGN

Signaling pathways activated by chelerythrine in osteosarcoma were detected by Western blots. Impacts of RAF/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK MAPK on apoptosis and cell survival were studied using genetic approaches and pharmacologic pathway-specific inhibitors.

RESULTS

Osteosarcoma cells underwent apoptosis rapidly after treatment with chelerythrine. Three parallel MAPKs pathways, including the ERKs, c-Jun NH(2) kinases, and p38, were activated by chelerythrine in a dose-dependent and time-dependent fashion. For the ERKs, the activation was evident at the earliest time point tested (2 minutes) and sustained for >4 hours. Introduction of a dominant-negative H-RAS mutant (17N) partially attenuated ERK activation and delayed the onset of apoptosis induced by chelerythrine. The ERK activation and apoptotic effects of chelerythrine were greatly abrogated by the pharmaceutical inhibitors of MEK, but not by those of c-Jun NH(2) kinase or p38. Moreover, osteosarcoma cells were sensitized to chelerythrine by transient transfection with wild-type MEK1 or constitutively active MEK1 and became resistant with dominant-negative MEK1. Other protein kinase C inhibitors, including GF109203X or Gö6976, did not cause ERK activation or apoptosis in the same timeframe tested.

CONCLUSION

In osteosarcoma, chelerythrine-induced apoptosis is mediated through activation of the RAF/MEK/ERK pathway. These findings suggest that activating the ERK MAPK, as opposed to inhibiting it, may be a therapeutic strategy in osteosarcoma.

Authors+Show Affiliations

Department of Pediatrics and Molecular Pharmacology, The Albert Einstein College of Medicine, The Children's Hospital at Montefiore, Bronx, New York 10467, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18927278

Citation

Yang, Rui, et al. "Activation of the RAF/mitogen-activated Protein/extracellular Signal-regulated Kinase Kinase/extracellular Signal-regulated Kinase Pathway Mediates Apoptosis Induced By Chelerythrine in Osteosarcoma." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 14, no. 20, 2008, pp. 6396-404.
Yang R, Piperdi S, Gorlick R. Activation of the RAF/mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase pathway mediates apoptosis induced by chelerythrine in osteosarcoma. Clin Cancer Res. 2008;14(20):6396-404.
Yang, R., Piperdi, S., & Gorlick, R. (2008). Activation of the RAF/mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase pathway mediates apoptosis induced by chelerythrine in osteosarcoma. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 14(20), 6396-404. https://doi.org/10.1158/1078-0432.CCR-07-5113
Yang R, Piperdi S, Gorlick R. Activation of the RAF/mitogen-activated Protein/extracellular Signal-regulated Kinase Kinase/extracellular Signal-regulated Kinase Pathway Mediates Apoptosis Induced By Chelerythrine in Osteosarcoma. Clin Cancer Res. 2008 Oct 15;14(20):6396-404. PubMed PMID: 18927278.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of the RAF/mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase pathway mediates apoptosis induced by chelerythrine in osteosarcoma. AU - Yang,Rui, AU - Piperdi,Sajida, AU - Gorlick,Richard, PY - 2008/10/18/pubmed PY - 2008/12/17/medline PY - 2008/10/18/entrez SP - 6396 EP - 404 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin. Cancer Res. VL - 14 IS - 20 N2 - PURPOSE: Chelerythrine, a widely used broad-range protein kinase C inhibitor, induces apoptosis in many cell types. In this study, the mechanism of chelerythrine-induced apoptosis in osteosarcoma was investigated. EXPERIMENTAL DESIGN: Signaling pathways activated by chelerythrine in osteosarcoma were detected by Western blots. Impacts of RAF/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK MAPK on apoptosis and cell survival were studied using genetic approaches and pharmacologic pathway-specific inhibitors. RESULTS: Osteosarcoma cells underwent apoptosis rapidly after treatment with chelerythrine. Three parallel MAPKs pathways, including the ERKs, c-Jun NH(2) kinases, and p38, were activated by chelerythrine in a dose-dependent and time-dependent fashion. For the ERKs, the activation was evident at the earliest time point tested (2 minutes) and sustained for >4 hours. Introduction of a dominant-negative H-RAS mutant (17N) partially attenuated ERK activation and delayed the onset of apoptosis induced by chelerythrine. The ERK activation and apoptotic effects of chelerythrine were greatly abrogated by the pharmaceutical inhibitors of MEK, but not by those of c-Jun NH(2) kinase or p38. Moreover, osteosarcoma cells were sensitized to chelerythrine by transient transfection with wild-type MEK1 or constitutively active MEK1 and became resistant with dominant-negative MEK1. Other protein kinase C inhibitors, including GF109203X or Gö6976, did not cause ERK activation or apoptosis in the same timeframe tested. CONCLUSION: In osteosarcoma, chelerythrine-induced apoptosis is mediated through activation of the RAF/MEK/ERK pathway. These findings suggest that activating the ERK MAPK, as opposed to inhibiting it, may be a therapeutic strategy in osteosarcoma. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/18927278/Activation_of_the_RAF/mitogen_activated_protein/extracellular_signal_regulated_kinase_kinase/extracellular_signal_regulated_kinase_pathway_mediates_apoptosis_induced_by_chelerythrine_in_osteosarcoma_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=18927278 DB - PRIME DP - Unbound Medicine ER -