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Selective regulation of expression of protein kinase C (PKC) isoenzymes in multidrug-resistant MCF-7 cells. Functional significance of enhanced expression of PKC alpha.

Publication ,  Journal Article
Blobe, GC; Sachs, CW; Khan, WA; Fabbro, D; Stabel, S; Wetsel, WC; Obeid, LM; Fine, RL; Hannun, YA
Published in: J Biol Chem
January 5, 1993

The multidrug resistance (MDR) phenotype induces cross-resistance to many chemotherapeutic agents in cancer cells. Protein kinase C (PKC) has been implicated in the regulation of the MDR phenotype. In order to determine the role of specific PKC isoenzymes in regulating the MDR phenotype, the expression and activity of PKC isoenzymes in the human breast cancer cell line, MCF-7-WT, and an MDR subline, MCF-7-MDR, were examined. The MDR phenotype was associated with a 10-fold increase in calcium-dependent PKC activity as well as a 10-fold decrease in calcium-independent activity was due to a selective increase in the activity was due to a selective increase in the expression of PKC alpha as determined by Western blot analysis and hydroxylapatite chromatography. This increase in expression of PKC alpha was regulated at the message level as demonstrated by Northern blot analysis. The decrease in calcium-independent activity was caused by a decrease in the expression of PCK delta and epsilon. The significance of the increase in PKC alpha expression was then demonstrated by a commensurate 11-fold increase in the basal and stimulated phosphorylation of the myristolated alanine-rich C kinase substrate. Phosphorylation of P-glycoprotein, the cellular mediator of the MDR phenotype, was increased > 20-fold in the unstimulated MCF-7-MDR cell line and its phosphorylation was further increased 2-fold in response to phorbol 12-myristate 13-acetate. These changes paralleled the increases in P-glycoprotein pump function and the MDR phenotype underscoring the role for PKC alpha in regulating P-glycoprotein phosphorylation and function.

Duke Scholars

Published In

J Biol Chem

ISSN

0021-9258

Publication Date

January 5, 1993

Volume

268

Issue

1

Start / End Page

658 / 664

Location

United States

Related Subject Headings

  • Vincristine
  • Vinblastine
  • Tumor Cells, Cultured
  • Tetradecanoylphorbol Acetate
  • RNA, Neoplasm
  • RNA, Messenger
  • Proteins
  • Protein Kinase C
  • Poly A
  • Phosphorylation
 

Citation

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Blobe, G. C., Sachs, C. W., Khan, W. A., Fabbro, D., Stabel, S., Wetsel, W. C., … Hannun, Y. A. (1993). Selective regulation of expression of protein kinase C (PKC) isoenzymes in multidrug-resistant MCF-7 cells. Functional significance of enhanced expression of PKC alpha. J Biol Chem, 268(1), 658–664.
Blobe, G. C., C. W. Sachs, W. A. Khan, D. Fabbro, S. Stabel, W. C. Wetsel, L. M. Obeid, R. L. Fine, and Y. A. Hannun. “Selective regulation of expression of protein kinase C (PKC) isoenzymes in multidrug-resistant MCF-7 cells. Functional significance of enhanced expression of PKC alpha.J Biol Chem 268, no. 1 (January 5, 1993): 658–64.
Blobe GC, Sachs CW, Khan WA, Fabbro D, Stabel S, Wetsel WC, Obeid LM, Fine RL, Hannun YA. Selective regulation of expression of protein kinase C (PKC) isoenzymes in multidrug-resistant MCF-7 cells. Functional significance of enhanced expression of PKC alpha. J Biol Chem. 1993 Jan 5;268(1):658–664.

Published In

J Biol Chem

ISSN

0021-9258

Publication Date

January 5, 1993

Volume

268

Issue

1

Start / End Page

658 / 664

Location

United States

Related Subject Headings

  • Vincristine
  • Vinblastine
  • Tumor Cells, Cultured
  • Tetradecanoylphorbol Acetate
  • RNA, Neoplasm
  • RNA, Messenger
  • Proteins
  • Protein Kinase C
  • Poly A
  • Phosphorylation