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Acetyl-CoA Counteracts the Inhibitory Effect of Antiandrogens on Androgen Receptor Signaling in Prostate Cancer Cells
Makhov, Peter Fazliyeva, Rushaniya Tufano, Antonio Cai, Kathy Q. Serebriiskii, Ilya Andrews, Andrew J. Kolenko, Vladimir M.
Makhov, Peter
Fazliyeva, Rushaniya
Tufano, Antonio
Cai, Kathy Q.
Serebriiskii, Ilya
Andrews, Andrew J.
Kolenko, Vladimir M.
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Journal article
Date
2022-11-29
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Cardiovascular Sciences
Cancer and Cellular Biology
Cancer and Cellular Biology
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http://dx.doi.org/10.3390/cancers14235900
Abstract
The commonly used therapeutic management of PC involves androgen deprivation therapy (ADT) followed by treatment with AR signaling inhibitors (ARSI). However, nearly all patients develop drug-resistant disease, with a median progression-free survival of less than 2 years in chemotherapy-naïve men. Acetyl-coenzyme A (acetyl-CoA) is a central metabolic signaling molecule with key roles in biosynthetic processes and cancer signaling. In signaling, acetyl-CoA serves as the acetyl donor for acetylation, a critical post-translational modification. Acetylation affects the androgen receptor (AR) both directly and indirectly increasing expression of AR dependent genes. Our studies reveal that PC cells respond to the treatment with ARSI by increasing expression of ATP-citrate lyase (ACLY), a major enzyme responsible for cytosolic acetyl-CoA synthesis, and up-regulation of acetyl-CoA intracellular levels. Inhibition of ACLY results in a significant suppression of ligand-dependent and -independent routes of AR activation. Accordingly, the addition of exogenous acetyl-CoA, or its precursor acetate, augments AR transcriptional activity and diminishes the anti-AR activity of ARSI. Taken together, our findings suggest that PC cells respond to antiandrogens by increasing activity of the acetyl-coA pathway in order to reinstate AR signaling.
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Makhov, P.; Fazliyeva, R.; Tufano, A.; Uzzo, R.G.; Cai, K.Q.; Serebriiskii, I.; Snyder, N.W.; Andrews, A.J.; Kolenko, V.M. Acetyl-CoA Counteracts the Inhibitory Effect of Antiandrogens on Androgen Receptor Signaling in Prostate Cancer Cells. Cancers 2022, 14, 5900. https://doi.org/10.3390/cancers14235900
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Cancers, Vol. 14, Iss. 23
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