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Published on: April 22, 2017
Differential regulation of protein expression, growth and apoptosis by natural and synthetic retinoids
M A Christine Pratt1, Minying Niu, Dawn White
1Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5. cpratt@uottawa.ca
Abstract:
All-trans retinoic acid (ATRA) can down regulate the anti-apoptotic protein Bcl-2 and the cell cycle proteins cyclin D1 and cdk2 in estrogen receptor-positive breast cancer cells. We show here that retinoids can also reduce expression of the inhibitor of apoptosis protein, survivin. Here we have compared the regulation of these proteins in MCF-7 and ZR-75 breast cancer cells by natural and synthetic retinoids selective for the RA receptors (RARs) alpha, beta, and gamma then correlated these with growth inhibition, induction of apoptosis and chemosensitization to Taxol. In both cell lines ATRA and 9-cis RA induced the most profound decreases in cyclin D1 and cdk2 expression and also mediated the largest growth inhibition. The RARalpha agonist, Ro 40-6055 also strongly downregulated these proteins although did not produce an equivalent decrease in S-phase cells. Only ATRA induced RARbeta expression. ATRA, 9-cis RA and 4-HPR initiated the highest level of apoptosis as determined by mitochondrial Bax translocation, while only ATRA and 9-cis RA strongly reduced Bcl-2 and survivin protein expression. Enumeration of dead cells over 96 h correlated well with downregulation of both survivin and Bcl-2. Simultaneous retinoid-mediated reduction of both these proteins also predicted optimal Taxol sensitization. 4-HPR was much weaker than the natural retinoids with respect to Taxol sensitization, consistent with the proposed requirement for reduced Bcl-2 in this synergy. Neither the extent of cell cycle protein regulation nor AP-1 inhibition fully predicted the antiproliferative effect of the synthetic retinoids suggesting that growth inhibition requires regulation of a spectrum of RAR-regulated gene products in addition even to pivotal cell cycle proteins.
Insights
Retinoids like ATRA and 9-cis RA effectively inhibit breast cancer cell growth by reducing anti-apoptotic proteins (Bcl-2, survivin) and cell cycle proteins (cyclin D1, cdk2). This downregulation enhances chemosensitization to Taxol.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Estrogen receptor-positive breast cancer cells are often treated with agents targeting cell proliferation and apoptosis.
- Retinoids, vitamin A derivatives, have shown potential in cancer therapy by modulating gene expression.
- Key proteins involved in cell survival (Bcl-2, survivin) and cell cycle progression (cyclin D1, cdk2) are frequently dysregulated in cancer.
Purpose of the Study:
- To investigate the effects of natural and synthetic retinoids on the expression of Bcl-2, survivin, cyclin D1, and cdk2 in breast cancer cells.
- To correlate retinoid-induced protein modulation with effects on cell growth, apoptosis, and chemosensitivity to Taxol.
- To compare the efficacy of different retinoids selective for retinoic acid receptors (RARs) alpha, beta, and gamma.
Main Methods:
- Treatment of MCF-7 and ZR-75 breast cancer cells with various retinoids, including all-trans retinoic acid (ATRA), 9-cis RA, and synthetic RAR agonists.
- Analysis of protein expression levels for Bcl-2, survivin, cyclin D1, and cdk2 using Western blotting or similar techniques.
- Assessment of cell growth inhibition, induction of apoptosis (e.g., via Bax translocation), and chemosensitization to Taxol.
Main Results:
- All-trans retinoic acid (ATRA) and 9-cis RA significantly decreased cyclin D1 and cdk2 expression, leading to substantial growth inhibition.
- Retinoids reduced the expression of anti-apoptotic proteins survivin and Bcl-2, with ATRA and 9-cis RA showing the strongest effects.
- Downregulation of survivin and Bcl-2 correlated with increased apoptosis and enhanced Taxol chemosensitization, particularly with ATRA and 9-cis RA.
Conclusions:
- Retinoids, especially ATRA and 9-cis RA, effectively inhibit estrogen receptor-positive breast cancer cell growth by downregulating critical cell cycle and anti-apoptotic proteins.
- The reduction in Bcl-2 and survivin expression by retinoids is crucial for sensitizing cancer cells to chemotherapy agents like Taxol.
- Optimal anti-proliferative effects may involve the regulation of a broader spectrum of RAR-targeted genes beyond just cell cycle proteins.
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