Extracellular protein kinase A as a cancer biomarker: Its expression by tumor cells and reversal by a myristate-lacking Cα and RIIβ subunit overexpression

Yee Sook Cho, Yun Gyu Park, Youl Nam Lee, Meyoung-Kon Kim, Susan Bates, Langzhu Tan, Yoon S. Cho-Chung

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85 Citations (Scopus)

Abstract

Overexpression of cAMP-dependent protein kinase (PKA) type I isozyme is associated with cell proliferation and neoplastic transformation. The presence of PKA on the external surface of LS-174T human colon carcinoma cells has been shown. Here, we show that cancer cells of various cell types excrete PKA into the conditioned medium. This extracellular PKA (ECPKA) is present in active, free catalytic subunit (C subunit) form, and its activity is specifically inhibited by PKA inhibitory protein, PKI. Overexpression of the Cα or RIα subunit gene of PKA in an expression vector, which upregulates intracellular PKA type I, markedly up-regulates ECPKA expression. In contrast, overexpression of the RIIβ subunit, which eliminates PKA type I, up-regulates PKA type II, and reverts the transformed phenotype, down- regulates ECPKA. A mutation in the Cα gene that prevents myristylation allows the intracellular PKA up-regulation but blocks the ECPKA increase, suggesting that the NH2-terminal myristyl group of Cα is required for the ECPKA expression. In serum of cancer patients, the ECPKA expression is up- regulated 10-fold as compared with normal serum. These results indicate that the ECPKA expression is an ordered cellular response of a living cell to actively exclude excess intracellular PKA molecules from the cell. This phenomenon is up-regulated in tumor cells and has an inverse relationship with the hormone dependency of breast cancer. Thus, the extracellular PKA may serve as a potential diagnostic and prognostic marker for cancer.

Original languageEnglish
Pages (from-to)835-840
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number2
DOIs
Publication statusPublished - 2000 Jan 18

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Myristic Acid
Tumor Biomarkers
Cyclic AMP-Dependent Protein Kinases
Protein Kinases
Neoplasms
Up-Regulation
Conditioned Culture Medium
Serum
Isoenzymes
Catalytic Domain
Colon
Proteins
Down-Regulation
Cell Proliferation
Hormones
Breast Neoplasms
Carcinoma
Phenotype
Mutation

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

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title = "Extracellular protein kinase A as a cancer biomarker: Its expression by tumor cells and reversal by a myristate-lacking Cα and RIIβ subunit overexpression",
abstract = "Overexpression of cAMP-dependent protein kinase (PKA) type I isozyme is associated with cell proliferation and neoplastic transformation. The presence of PKA on the external surface of LS-174T human colon carcinoma cells has been shown. Here, we show that cancer cells of various cell types excrete PKA into the conditioned medium. This extracellular PKA (ECPKA) is present in active, free catalytic subunit (C subunit) form, and its activity is specifically inhibited by PKA inhibitory protein, PKI. Overexpression of the Cα or RIα subunit gene of PKA in an expression vector, which upregulates intracellular PKA type I, markedly up-regulates ECPKA expression. In contrast, overexpression of the RIIβ subunit, which eliminates PKA type I, up-regulates PKA type II, and reverts the transformed phenotype, down- regulates ECPKA. A mutation in the Cα gene that prevents myristylation allows the intracellular PKA up-regulation but blocks the ECPKA increase, suggesting that the NH2-terminal myristyl group of Cα is required for the ECPKA expression. In serum of cancer patients, the ECPKA expression is up- regulated 10-fold as compared with normal serum. These results indicate that the ECPKA expression is an ordered cellular response of a living cell to actively exclude excess intracellular PKA molecules from the cell. This phenomenon is up-regulated in tumor cells and has an inverse relationship with the hormone dependency of breast cancer. Thus, the extracellular PKA may serve as a potential diagnostic and prognostic marker for cancer.",
author = "Cho, {Yee Sook} and Park, {Yun Gyu} and Lee, {Youl Nam} and Meyoung-Kon Kim and Susan Bates and Langzhu Tan and Cho-Chung, {Yoon S.}",
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T2 - Its expression by tumor cells and reversal by a myristate-lacking Cα and RIIβ subunit overexpression

AU - Cho, Yee Sook

AU - Park, Yun Gyu

AU - Lee, Youl Nam

AU - Kim, Meyoung-Kon

AU - Bates, Susan

AU - Tan, Langzhu

AU - Cho-Chung, Yoon S.

PY - 2000/1/18

Y1 - 2000/1/18

N2 - Overexpression of cAMP-dependent protein kinase (PKA) type I isozyme is associated with cell proliferation and neoplastic transformation. The presence of PKA on the external surface of LS-174T human colon carcinoma cells has been shown. Here, we show that cancer cells of various cell types excrete PKA into the conditioned medium. This extracellular PKA (ECPKA) is present in active, free catalytic subunit (C subunit) form, and its activity is specifically inhibited by PKA inhibitory protein, PKI. Overexpression of the Cα or RIα subunit gene of PKA in an expression vector, which upregulates intracellular PKA type I, markedly up-regulates ECPKA expression. In contrast, overexpression of the RIIβ subunit, which eliminates PKA type I, up-regulates PKA type II, and reverts the transformed phenotype, down- regulates ECPKA. A mutation in the Cα gene that prevents myristylation allows the intracellular PKA up-regulation but blocks the ECPKA increase, suggesting that the NH2-terminal myristyl group of Cα is required for the ECPKA expression. In serum of cancer patients, the ECPKA expression is up- regulated 10-fold as compared with normal serum. These results indicate that the ECPKA expression is an ordered cellular response of a living cell to actively exclude excess intracellular PKA molecules from the cell. This phenomenon is up-regulated in tumor cells and has an inverse relationship with the hormone dependency of breast cancer. Thus, the extracellular PKA may serve as a potential diagnostic and prognostic marker for cancer.

AB - Overexpression of cAMP-dependent protein kinase (PKA) type I isozyme is associated with cell proliferation and neoplastic transformation. The presence of PKA on the external surface of LS-174T human colon carcinoma cells has been shown. Here, we show that cancer cells of various cell types excrete PKA into the conditioned medium. This extracellular PKA (ECPKA) is present in active, free catalytic subunit (C subunit) form, and its activity is specifically inhibited by PKA inhibitory protein, PKI. Overexpression of the Cα or RIα subunit gene of PKA in an expression vector, which upregulates intracellular PKA type I, markedly up-regulates ECPKA expression. In contrast, overexpression of the RIIβ subunit, which eliminates PKA type I, up-regulates PKA type II, and reverts the transformed phenotype, down- regulates ECPKA. A mutation in the Cα gene that prevents myristylation allows the intracellular PKA up-regulation but blocks the ECPKA increase, suggesting that the NH2-terminal myristyl group of Cα is required for the ECPKA expression. In serum of cancer patients, the ECPKA expression is up- regulated 10-fold as compared with normal serum. These results indicate that the ECPKA expression is an ordered cellular response of a living cell to actively exclude excess intracellular PKA molecules from the cell. This phenomenon is up-regulated in tumor cells and has an inverse relationship with the hormone dependency of breast cancer. Thus, the extracellular PKA may serve as a potential diagnostic and prognostic marker for cancer.

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