Targeting the glutamine metabolism to suppress cell proliferation in mesenchymal docetaxel-resistant prostate cancer.
Alicia-Marie K BeierCelina EbersbachTiziana SicilianoJana ScholzeJörg HofmannPia HönscheidGustavo B BarettonKevin WoodsBorhane GuezguezAnna DubrovskaSascha D MarkowitschChristian ThomasMartin PuhrHolger Hans Hermann ErbPublished in: Oncogene (2024)
Docetaxel (DX) serves as a palliative treatment option for metastatic prostate cancer (PCa). Despite initial remission, acquired DX resistance is inevitable. The mechanisms behind DX resistance have not yet been deciphered, but a mesenchymal phenotype is associated with DX resistance. Mesenchymal phenotypes have been linked to metabolic rewiring, obtaining most ATP production by oxidative phosphorylation (OXPHOS) powered substantially by glutamine (Gln). Likewise, Gln is known to play an essential role in modulating bioenergetic, redox homeostasis and autophagy. Herein, investigations of Gln deprivation on DX-sensitive and -resistant (DR) PCa cells revealed that the DR cell sub-lines were susceptible to Gln deprivation. Mechanistically, Gln deprivation reduced OXPHOS and ATP levels, causing a disturbance in cell cycle progression. Genetic and chemical inhibition of the Gln-metabolism key protein GLS1 could validate the Gln deprivation results, thereby representing a valid therapeutic target. Moreover, immunohistological investigation of GLS1 revealed a high-expressing GLS1 subgroup post-docetaxel failure, exhibiting low overall survival. This subgroup presents an intriguing opportunity for targeted therapy focusing on glutamine metabolism. Thus, these findings highlight a possible clinical rationale for the chemical inhibition of GLS1 as a therapeutic strategy to target mesenchymal DR PCa cells, thereby delaying accelerated tumour progression.
Keyphrases
- prostate cancer
- cell cycle
- cell proliferation
- bone marrow
- stem cells
- induced apoptosis
- cell cycle arrest
- single cell
- radical prostatectomy
- signaling pathway
- editorial comment
- cell death
- locally advanced
- small cell lung cancer
- oxidative stress
- squamous cell carcinoma
- clinical trial
- palliative care
- gene expression
- small molecule
- pi k akt
- rheumatoid arthritis
- dna methylation
- rectal cancer
- genome wide
- ulcerative colitis
- protein protein