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Lack of modulation of MDR1 gene expression by dominant inhibition of cAMP‐dependent protein kinase in doxorubicin‐resistant mcf‐7 breast cancer cells
Author(s) -
Parissenti Amadeo M.,
Gan Brian R.,
Villeneuve David J.,
Kirwanrhude Angela F.,
Chadderton Antony,
Glück Stefan
Publication year - 1999
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19990909)82:6<893::aid-ijc20>3.0.co;2-8
Subject(s) - mcf 7 , doxorubicin , protein kinase a , cancer research , breast cancer , gene , gene expression , kinase , biology , cancer , medicine , human breast , chemotherapy , microbiology and biotechnology , genetics
Abstract The drug transporter P‐glycoprotein (P‐gp) appears to play an important role in the ability of tumor cells to evade killing by chemotherapeutic agents. Using pharmacological inhibitors of cAMP‐dependent protein kinase (PKA), it has been suggested that, similar to rodent model systems, the human P‐gp gene ( MDR1 ) is also under PKA‐dependent control and that PKA inhibition may prove useful in reducing drug resistance in human cancer cells. To test this hypothesis, we stably transformed doxorubicin (Adriamycin)‐resistant human MCF‐7 breast cancer cells (MCF‐7 ADR ) with a vector that inhibits PKA activity by inducing over‐expression of mutant type Iα PKA regulatory (RIα) subunits. Two transformants (MCF‐7 ADR‐A and MCF‐7 ADR‐B ) were found to express mutant RIα subunits and to possess markedly reduced PKA activity; another transformant (MCF‐7 ADR‐9 ) lacked mutant RIα subunit expression and exhibited no inhibition of PKA activity. In contrast with findings in Chinese hamster ovary and Y1 adrenal cells, P‐gp levels and cellular sensitivity to drugs which are P‐gp substrates were unchanged in the PKA‐inhibited transformants, suggesting that P‐gp expression and function are not under PKA‐dependent control in MCF‐7 ADR cells. Growth and saturation densities of the cell lines were highly correlated with level of PKA catalytic activity, suggesting that PKA inhibition may prove useful in inhibiting growth of breast tumor cells, even upon establishment of resistance to doxorubicin. However, our results challenge current proposals that drug sensitivity in P‐gp‐expressing human tumor cells may be restored by blocking MDR1 gene expression through inhibition of PKA activity. Int. J. Cancer 82:893–900, 1999. © 1999 Wiley‐Liss, Inc.