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Transcriptional regulation of multidrug resistance in breast cancer
1Georgetown University Medical Center, Department of Pharmacology, Washington, DC 20007.
Abstract:
The development of cross-resistance to many natural product anticancer drugs, termed multidrug resistance (MDR), is one of the major reasons why cancer chemotherapy ultimately fails. This type of MDR is often associated with over-expression of the MDR1 gene product, P-glycoprotein (Pgp), a multifunctional drug transporter. The expression of MDR in breast tumors is related to their origination from a tissue that constitutively expresses Pgp as well as to the development of resistance during successive courses of chemotherapy. Therefore, understanding the mechanisms that regulate the transcriptional activation of MDR1 may afford a means of reducing or eliminating MDR. We have found that MDR1 expression can be modulated by type I cAMP-dependent protein kinase (PKA), opening up the possibility of modulating MDR by selectively down-regulating the activity of PKA-dependent transcription factors which upregulate MDR1 expression. High levels of type I PKA occurs in primary breast carcinomas and patients exhibiting this phenotype show decreased survival. The selective type I cAMP-dependent protein kinase (PKA) inhibitors, 8-Cl-cAMP and Rp8-Cl-cAMP[S] may be particularly useful for downregulating PKA-dependent MDR-associated transcription factors, and we have found these compounds to downregulate transient expression of a reporter gene under the control of several MDR1 promoter elements. Thus, investigations of this nature should not only lead to a greater understanding of the mechanisms governing the expression of MDR, but also provide a focus for pharmacologic intervention by a new class of inhibitors.
Insights
Multidrug resistance (MDR) in cancer chemotherapy failure can be targeted by inhibiting type I cAMP-dependent protein kinase (PKA). Selective PKA inhibitors downregulate MDR1 gene expression, offering a new therapeutic strategy.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Multidrug resistance (MDR) is a significant challenge in cancer chemotherapy, often linked to P-glycoprotein (Pgp) overexpression.
- MDR1 gene expression in breast tumors is influenced by tissue origin and chemotherapy resistance development.
- Understanding MDR1 transcriptional regulation is crucial for overcoming chemotherapy failure.
Purpose of the Study:
- To investigate the role of type I cAMP-dependent protein kinase (PKA) in regulating MDR1 gene expression.
- To explore the potential of PKA inhibitors as a therapeutic strategy against MDR.
Main Methods:
- Assessed the modulation of MDR1 expression by type I PKA.
- Investigated the effect of selective type I PKA inhibitors (8-Cl-cAMP and Rp8-Cl-cAMP[S]) on MDR1 promoter activity using a reporter gene assay.
Main Results:
- Type I PKA influences MDR1 expression, suggesting a pathway for MDR modulation.
- High type I PKA levels correlate with decreased survival in breast carcinoma patients.
- Selective type I PKA inhibitors effectively downregulated reporter gene expression driven by MDR1 promoter elements.
Conclusions:
- Targeting type I PKA offers a potential strategy to overcome MDR in cancer.
- Selective PKA inhibitors show promise for pharmacologic intervention against MDR-associated transcription factors.
- Further research into PKA-dependent pathways can enhance understanding and treatment of MDR.