Effects of protein kinase C activators on phorbol ester-sensitive and -resistant EL4 thymoma cells

H M Sansbury; A E Wisehart-Johnson; C Qi; S Fulwood; K E Meier

doi:10.1093/carcin/18.9.1817

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Effects of protein kinase C activators on phorbol ester-sensitive and -resistant EL4 thymoma cells

Journal article

Open access

Peer reviewed

Effects of protein kinase C activators on phorbol ester-sensitive and -resistant EL4 thymoma cells

H M Sansbury, A E Wisehart-Johnson, C Qi, S Fulwood and K E Meier

Carcinogenesis (New York), Vol.18(9), pp.1817-1824

09/1997

DOI: https://doi.org/10.1093/carcin/18.9.1817

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https://hdl.handle.net/2376/105132

PMID: 9328180

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Abstract

Animals

Tetradecanoylphorbol Acetate - pharmacology

Biological Transport

Ribosomal Protein S6 Kinases - metabolism

Thymoma

Protein Kinase C - metabolism

Drug Resistance, Neoplasm

Mice

Enzyme Activation

Tumor Cells, Cultured

Calcium-Calmodulin-Dependent Protein Kinases - metabolism

Phorbol ester-sensitive EL4 murine thymoma cells respond to phorbol 12-myristate 13-acetate with activation of ERK mitogen-activated protein kinases, synthesis of interleukin-2, and death, whereas phorbol ester-resistant variants of this cell line do not exhibit these responses. Additional aspects of the resistant phenotype were examined, using a newly-established resistant cell line. Phorbol ester induced morphological changes, ERK activation, calcium-dependent activation of the c-Jun N-terminal kinase (JNK), interleukin-2 synthesis, and growth inhibition in sensitive but not resistant cells. A series of protein kinase C activators caused membrane translocation of protein kinase C's (PKCs) alpha, eta, and theta in both cell lines. While PKC eta was expressed at higher levels in sensitive than in resistant cells, overexpression of PKC eta did not restore phorbol ester-induced ERK activation to resistant cells. In sensitive cells, PKC activators had similar effects on cell viability and ERK activation, but differed in their abilities to induce JNK activation and interleukin-2 synthesis. PD 098059, an inhibitor of the mitogen activated protein (MAP)/ERK kinase kinase MEK, partially inhibited ERK activation and completely blocked phorbol ester-induced cell death in sensitive cells. Thus MEK and/or ERK activation, but not JNK activation or interleukin-2 synthesis, appears to be required for phorbol ester-induced toxicity. Alterations in phorbol ester response pathways, rather than altered expression of PKC isoforms, appear to confer phorbol ester resistance to EL4 cells.

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Title: Effects of protein kinase C activators on phorbol ester-sensitive and -resistant EL4 thymoma cells
Creators: H M Sansbury - Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston 29425-2251, USA
A E Wisehart-Johnson
C Qi
S Fulwood
K E Meier
Publication Details: Carcinogenesis (New York), Vol.18(9), pp.1817-1824
Academic Unit: Pharmaceutical Sciences, Department of
Publisher: England
Grant note: CA58640 / NCI NIH HHS
Identifiers: 99900546690301842
Language: English
Resource Type: Journal article