Effects of bryostatin 1, a novel anticancer agent, on intestinal transport and barrier function: Role of protein kinase C

O. C. Farokhzad, E. C. Mun, J. K. Sicklick, J. A. Smith, J. B. Matthews, David Soybel, A. H. Harken

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Background. Bryostatin 1 is a novel chemotherapeutic agent that activates specific members of the protein kinase C (PKC) family in a complex pattern overlapping with, but distinct from, that of tumor-promoting phorbol esters. Phorbol esters profoundly alter epithelial phenotype, abolishing both barrier function and Cl secretion (the latter due to loss of a key transport site, the Na-K-Cl cotransporter). The effects of bryostatin 1 on these parameters are unknown. Methods. Cl secretion and barrier function of T84 human intestinal epithelia were assessed as cyclic adenosine monophosphate- stimulated short-circuit current and transepithelial resistance, respectively. Na-K-Cl cotransporter function and mRNA expression were assayed by 86Rb uptake and Northern analysis. Results. Bryostatin 1 reduced Cl secretion, Na-K-Cl cotransport, and cotransporter mRNA expression. Unlike phorbol esters, these effects were largely transient. In contrast to phorbol esters, bryostatin 1 did not decrease barrier function. Conclusions. Bryostatin 1 transiently inhibits Na-K-Cl cotransport and Cl secretion, possibly through a PKC isoform also targeted by phorbol esters. Unlike phorbol esters, bryostatin 1 does not impair barrier function. The data imply that bryostatin 1 and phorbol esters differentially affect a PKC isoform involved in junctional regulation, and that epithelial transport and barrier function may be regulated by distinct PKC isoforms.

Original languageEnglish (US)
Pages (from-to)380-387
Number of pages8
JournalSurgery
Volume124
Issue number2
DOIs
StatePublished - Jan 1 1998

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Phorbol Esters
Antineoplastic Agents
Protein Kinase C
Sodium-Potassium-Chloride Symporters
Protein Isoforms
Messenger RNA
Intestinal Mucosa
bryostatin 1
Cyclic AMP
Phenotype
Neoplasms

All Science Journal Classification (ASJC) codes

  • Surgery

Cite this

Farokhzad, O. C. ; Mun, E. C. ; Sicklick, J. K. ; Smith, J. A. ; Matthews, J. B. ; Soybel, David ; Harken, A. H. / Effects of bryostatin 1, a novel anticancer agent, on intestinal transport and barrier function : Role of protein kinase C. In: Surgery. 1998 ; Vol. 124, No. 2. pp. 380-387.
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Effects of bryostatin 1, a novel anticancer agent, on intestinal transport and barrier function : Role of protein kinase C. / Farokhzad, O. C.; Mun, E. C.; Sicklick, J. K.; Smith, J. A.; Matthews, J. B.; Soybel, David; Harken, A. H.

In: Surgery, Vol. 124, No. 2, 01.01.1998, p. 380-387.

Research output: Contribution to journalArticle

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T1 - Effects of bryostatin 1, a novel anticancer agent, on intestinal transport and barrier function

T2 - Role of protein kinase C

AU - Farokhzad, O. C.

AU - Mun, E. C.

AU - Sicklick, J. K.

AU - Smith, J. A.

AU - Matthews, J. B.

AU - Soybel, David

AU - Harken, A. H.

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N2 - Background. Bryostatin 1 is a novel chemotherapeutic agent that activates specific members of the protein kinase C (PKC) family in a complex pattern overlapping with, but distinct from, that of tumor-promoting phorbol esters. Phorbol esters profoundly alter epithelial phenotype, abolishing both barrier function and Cl secretion (the latter due to loss of a key transport site, the Na-K-Cl cotransporter). The effects of bryostatin 1 on these parameters are unknown. Methods. Cl secretion and barrier function of T84 human intestinal epithelia were assessed as cyclic adenosine monophosphate- stimulated short-circuit current and transepithelial resistance, respectively. Na-K-Cl cotransporter function and mRNA expression were assayed by 86Rb uptake and Northern analysis. Results. Bryostatin 1 reduced Cl secretion, Na-K-Cl cotransport, and cotransporter mRNA expression. Unlike phorbol esters, these effects were largely transient. In contrast to phorbol esters, bryostatin 1 did not decrease barrier function. Conclusions. Bryostatin 1 transiently inhibits Na-K-Cl cotransport and Cl secretion, possibly through a PKC isoform also targeted by phorbol esters. Unlike phorbol esters, bryostatin 1 does not impair barrier function. The data imply that bryostatin 1 and phorbol esters differentially affect a PKC isoform involved in junctional regulation, and that epithelial transport and barrier function may be regulated by distinct PKC isoforms.

AB - Background. Bryostatin 1 is a novel chemotherapeutic agent that activates specific members of the protein kinase C (PKC) family in a complex pattern overlapping with, but distinct from, that of tumor-promoting phorbol esters. Phorbol esters profoundly alter epithelial phenotype, abolishing both barrier function and Cl secretion (the latter due to loss of a key transport site, the Na-K-Cl cotransporter). The effects of bryostatin 1 on these parameters are unknown. Methods. Cl secretion and barrier function of T84 human intestinal epithelia were assessed as cyclic adenosine monophosphate- stimulated short-circuit current and transepithelial resistance, respectively. Na-K-Cl cotransporter function and mRNA expression were assayed by 86Rb uptake and Northern analysis. Results. Bryostatin 1 reduced Cl secretion, Na-K-Cl cotransport, and cotransporter mRNA expression. Unlike phorbol esters, these effects were largely transient. In contrast to phorbol esters, bryostatin 1 did not decrease barrier function. Conclusions. Bryostatin 1 transiently inhibits Na-K-Cl cotransport and Cl secretion, possibly through a PKC isoform also targeted by phorbol esters. Unlike phorbol esters, bryostatin 1 does not impair barrier function. The data imply that bryostatin 1 and phorbol esters differentially affect a PKC isoform involved in junctional regulation, and that epithelial transport and barrier function may be regulated by distinct PKC isoforms.

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