Delineating the Role of the Acetyl-CoA Pathway in the Resistance to Anti-Androgen Therapy
Abstract
Despite significant efforts, overcoming resistance to therapeutics targeting the androgen receptor (AR) axis remains an unmet medical need. During the last year, we were conducting studies to test the novel hypothesis that prostate cancer (PC) cells upregulate production of acetyl-CoA as an adaptive defense mechanism in response to androgen deprivation. Our recent studies support our initial hypothesis demonstrating that the enhancement of acetyl-CoA supply increases AR transcriptional activity and viability of PC cells cultured under androgen deprived conditions. In contrary, AR transcriptional activity was significantly reduced in PC cells carrying individual or combined knockdowns of acetyltransferases p300 and CBP. Importantly, the expression of the two major enzymes that produce acetyl-CoA, ATP-citrate lyase (ACLY), which generates acetyl-CoA from mitochondria derived citrate, and acetyl-CoA synthetase 2 (ACSS2), which produces acetyl-CoA from acetate was significantly enhanced in androgen-dependent and castration-resistant PC cells following androgen-deprivation. In addition, immunohistochemical analysis revealed that the expression of both ACLY and ACSS2 was significantly elevated in PC tissue compared with normal prostate tissue. Taken together, these findings suggest that aberrant acetyl-CoA homeostasis may play a critical role in the development of primary and acquired resistance to therapeutics targeting AR signaling.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2023
- Accession Number
- AD1216454
Entities
People
- Vladimir Kolenko
Organizations
- Fox Chase Cancer Center