Targeting prostate tumor low-molecular weight tyrosine phosphatase for oxidation-sensitizing therapy.
Stephanie M StanfordTiffany P NguyenJoseph ChangZixuan ZhaoG Lavender HackmanEugenio SantelliColton M SandersMadhusudhanarao KatikiEleonora DondossolaBrooke L BrauerMichael A DiazYuan ZhanSterling H RamseyPhilip A WatsonBanumathi SankaranClaudia PaindelliVanessa PariettiAntonios G MikosAlessia LodiAditya BagrodiaAndrew ElliottRana R McKayRamachandran MuraliStefano TizianiArminja N KettenbachNunzio BottiniPublished in: Science advances (2024)
Protein tyrosine phosphatases (PTPs) play major roles in cancer and are emerging as therapeutic targets. Recent reports suggest low-molecular weight PTP (LMPTP)-encoded by the ACP1 gene-is overexpressed in prostate tumors. We found ACP1 up-regulated in human prostate tumors and ACP1 expression inversely correlated with overall survival. Using CRISPR-Cas9-generated LMPTP knockout C4-2B and MyC-CaP cells, we identified LMPTP as a critical promoter of prostate cancer (PCa) growth and bone metastasis. Through metabolomics, we found that LMPTP promotes PCa cell glutathione synthesis by dephosphorylating glutathione synthetase on inhibitory Tyr 270 . PCa cells lacking LMPTP showed reduced glutathione, enhanced activation of eukaryotic initiation factor 2-mediated stress response, and enhanced reactive oxygen species after exposure to taxane drugs. LMPTP inhibition slowed primary and bone metastatic prostate tumor growth in mice. These findings reveal a role for LMPTP as a critical promoter of PCa growth and metastasis and validate LMPTP inhibition as a therapeutic strategy for treating PCa through sensitization to oxidative stress.
Keyphrases
- prostate cancer
- induced apoptosis
- radical prostatectomy
- crispr cas
- oxidative stress
- transcription factor
- benign prostatic hyperplasia
- reactive oxygen species
- dna methylation
- cell cycle arrest
- gene expression
- bone mineral density
- squamous cell carcinoma
- endothelial cells
- small cell lung cancer
- genome wide
- poor prognosis
- genome editing
- emergency department
- stem cells
- papillary thyroid
- insulin resistance
- soft tissue
- single cell
- copy number
- adipose tissue
- cell death
- binding protein
- postmenopausal women
- cancer therapy
- ischemia reperfusion injury
- cell therapy
- nitric oxide
- bone marrow
- metabolic syndrome
- small molecule
- protein protein
- drug induced
- smoking cessation
- protein kinase