We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Androgen receptor-dependent regulation of metabolism in high grade bladder cancer cells.
- Authors
Katleba, Kimberley D.; Tsamouri, Maria-Malvina; Jathal, Maitreyee; Baek, Han Bit; Armenta, Rebecca B.; Tepper, Clifford G.; Cortopassi, Gino; Ghosh, Paramita M.; Mudryj, Maria
- Abstract
The observed sex disparity in bladder cancer (BlCa) argues that androgen receptor (AR) signaling has a role in these malignancies. BlCas express full-length AR (FL-AR), constitutively active AR splice variants, including AR-v19, or both, and their depletion limits BlCa viability. However, the mechanistic basis of AR-dependence is unknown. Here, we depleted FL-AR, AR-v19, or all AR forms (T-AR), and performed RNA-seq studies to uncover that different AR forms govern distinct but partially overlapping transcriptional programs. Overlapping alterations include a decrease in mTOR and an increase of hypoxia regulated transcripts accompanied by a decline in oxygen consumption rate (OCR). Queries of BlCa databases revealed a significant negative correlation between AR expression and multiple hypoxia-associated transcripts arguing that this regulatory mechanism is a feature of high-grade malignancies. Our analysis of a 1600-compound library identified niclosamide as a strong ATPase inhibitor that reduces OCR in BlCa cells, decreased cell viability and induced apoptosis in a dose and time dependent manner. These results suggest that BlCa cells hijack AR signaling to enhance metabolic activity, promoting cell proliferation and survival; hence targeting this AR downstream vulnerability presents an attractive strategy to limit BlCa.
- Subjects
METABOLIC regulation; BLADDER cancer; CANCER cells; ANDROGEN receptors; ANDROGENS; OXYGEN consumption; CELL survival
- Publication
Scientific Reports, 2023, Vol 13, Issue 1, p1
- ISSN
2045-2322
- Publication type
Article
- DOI
10.1038/s41598-023-28692-z