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Inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase enhances chemotherapeutic effects on H460 human non-small cell lung cancer cells through activation of apoptosis.
Mol Cancer Ther. 2003 Jul; 2(7):641-9.MC

Abstract

The effects of Dox (Dox), paclitaxel (Taxol), and serum starvation on the regulation of XIAP (X-linked inhibitor of apoptosis), Bcl-2 phosphorylation, and apoptosis were evaluated in human H460 non-small cell lung cancer cells. Protein kinases that responded to these treatments as prosurvival elements in signal transduction were identified by simultaneously screening phosphorylation of protein kinases in H460 cells cultured in serum-free medium or treated with Dox. We demonstrated that Dox and Taxol induced apoptosis through down-regulation of XIAP and phosphorylation of Bcl-2 in a concentration-dependent manner without changing expression of Bcl-xL in H460 cells. These effects were paralleled by activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase protein. We identified that serum starvation and Dox reduced phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK), protein kinase C (PKC) alpha/beta and c-Jun NH(2)-terminal kinase. The MEK-specific inhibitor U0126 or PKC inhibitor staurosporine (STP) also down-regulated XIAP expression and induced apoptosis. Thus, our data suggest that apoptosis and down-regulation of XIAP induced by Dox exposure or serum starvation may be mediated through inactivation of the MEK/ERK and PKCalpha/beta pathways. In support of this we demonstrated that the cytotoxic effects of Dox when combined with U0126 or STP were enhanced, i.e., synergistic cytotoxic activities were demonstrated. The synergistic interaction of U0126 or STP with Dox was sequence- and concentration-dependent.

Authors+Show Affiliations

Department of Advanced Therapeutics, British Columbia Cancer Agency, Vancouver, British Columbia, V5Z 4E6 Canada.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12883037

Citation

Hu, Yanping, et al. "Inhibition of Mitogen-activated Protein Kinase/extracellular Signal-regulated Kinase Kinase Enhances Chemotherapeutic Effects On H460 Human Non-small Cell Lung Cancer Cells Through Activation of Apoptosis." Molecular Cancer Therapeutics, vol. 2, no. 7, 2003, pp. 641-9.
Hu Y, Bally M, Dragowska WH, et al. Inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase enhances chemotherapeutic effects on H460 human non-small cell lung cancer cells through activation of apoptosis. Mol Cancer Ther. 2003;2(7):641-9.
Hu, Y., Bally, M., Dragowska, W. H., & Mayer, L. (2003). Inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase enhances chemotherapeutic effects on H460 human non-small cell lung cancer cells through activation of apoptosis. Molecular Cancer Therapeutics, 2(7), 641-9.
Hu Y, et al. Inhibition of Mitogen-activated Protein Kinase/extracellular Signal-regulated Kinase Kinase Enhances Chemotherapeutic Effects On H460 Human Non-small Cell Lung Cancer Cells Through Activation of Apoptosis. Mol Cancer Ther. 2003;2(7):641-9. PubMed PMID: 12883037.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase enhances chemotherapeutic effects on H460 human non-small cell lung cancer cells through activation of apoptosis. AU - Hu,Yanping, AU - Bally,Marcel, AU - Dragowska,Wieslawa H, AU - Mayer,Lawrence, PY - 2003/7/29/pubmed PY - 2004/4/24/medline PY - 2003/7/29/entrez SP - 641 EP - 9 JF - Molecular cancer therapeutics JO - Mol. Cancer Ther. VL - 2 IS - 7 N2 - The effects of Dox (Dox), paclitaxel (Taxol), and serum starvation on the regulation of XIAP (X-linked inhibitor of apoptosis), Bcl-2 phosphorylation, and apoptosis were evaluated in human H460 non-small cell lung cancer cells. Protein kinases that responded to these treatments as prosurvival elements in signal transduction were identified by simultaneously screening phosphorylation of protein kinases in H460 cells cultured in serum-free medium or treated with Dox. We demonstrated that Dox and Taxol induced apoptosis through down-regulation of XIAP and phosphorylation of Bcl-2 in a concentration-dependent manner without changing expression of Bcl-xL in H460 cells. These effects were paralleled by activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase protein. We identified that serum starvation and Dox reduced phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK), protein kinase C (PKC) alpha/beta and c-Jun NH(2)-terminal kinase. The MEK-specific inhibitor U0126 or PKC inhibitor staurosporine (STP) also down-regulated XIAP expression and induced apoptosis. Thus, our data suggest that apoptosis and down-regulation of XIAP induced by Dox exposure or serum starvation may be mediated through inactivation of the MEK/ERK and PKCalpha/beta pathways. In support of this we demonstrated that the cytotoxic effects of Dox when combined with U0126 or STP were enhanced, i.e., synergistic cytotoxic activities were demonstrated. The synergistic interaction of U0126 or STP with Dox was sequence- and concentration-dependent. SN - 1535-7163 UR - https://www.unboundmedicine.com/medline/citation/12883037/Inhibition_of_mitogen_activated_protein_kinase/extracellular_signal_regulated_kinase_kinase_enhances_chemotherapeutic_effects_on_H460_human_non_small_cell_lung_cancer_cells_through_activation_of_apoptosis_ L2 - http://mct.aacrjournals.org/cgi/pmidlookup?view=long&pmid=12883037 DB - PRIME DP - Unbound Medicine ER -