Acetyl-CoA Counteracts the Inhibitory Effect of Antiandrogens on Androgen Receptor Signaling in Prostate Cancer Cells
Year: 2022
Type: article
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.
Source: Cancers
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,513
Awards: G1022998031, G1054388225, G1303292201, G2186300445, G2815785733, G3092267087, G3874596251, G4004123761, Novel anti-CD70-VEGF-trap fusion antibodies as a next-generation therapeutic approach for renal cancer, G501207485, G5136518482, G5878942408, G6138703056, G6521172226, Tumor-specific anti-angiogenic anti-CD70-FGF/VEGF-trap fusion antibodies for renal cancer therapy, G7238519783, The Role of Histone Chaperones in Histone Acetylation and Nucleosome Dynamics, Disrupting lysosomal sequestration of sunitinib by farnesyl-transferase inhibitors as a next generation therapeutic approach for TKI resistant RCC, The role of cholesterol homeostasis in enzalutamide resistance, G9000079751, Comprehensive Cancer Center Program at Fox Chase
OpenAlex ID: W4311009825