PRPS1 silencing reverses cisplatin resistance in human breast cancer cells.
PRPS1 (phosphoribosyl pyrophosphate synthetase 1), which drives the nucleotide biosynthesis pathway, modulates a variety of functions by providing central building blocks and cofactors for cell homeostasis. As tumor cells often display abnormal nucleotide metabolism, dysregulated de-novo nucleotide synthesis has potential impacts in cancers. We now report that PRPS1 is specifically and highly expressed in chemoresistant (CR) cancer cells derived from cisplatin-resistant human breast cancer cell lines SK-BR-3 and MCF-7. The inhibition of PRPS1 activity in CR cells by genetic silencing reduces cell viability and increases apoptosis in vitro, both of which can be further potentiated by cisplatin treatment. Significantly, such down-regulation of PRPS1 in CR cells when administered to nude mice enhanced the survival of those animals, as demonstrated by decreased tumor growth. Knockdown of PRPSI may cause these effects by potently inducing autonomous activation of caspase-3 and inhibiting the proliferation in the engrafted CR tumors. As a result, cisplatin sensitivity in a xenograft model of CR cancer cells can be restored by the down-regulation of PRPS1. Thus, PRPS1 inhibition may afford a therapeutic approach to relapsed patients with breast cancer, resistant to chemotherapy.
a Department of Breast Surgery, Wuxi Second People's Hospital, Wuxi 214000, China.
Min
M
He
a Department of Breast Surgery, Wuxi Second People's Hospital, Wuxi 214000, China.
Lin
L
Chao
b Department of Neurology, Wuxi People's Hospital, Wuxi 214000, China.
Yi-Ping
YP
You
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012268:Ribose-Phosphate Pyrophosphokinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C510474:PRPS1 protein, human; D012268:Ribose-Phosphate Pyrophosphokinase; D002945:Cisplatin
PRPS1; breast cancer; cancer du sein; cisplatin; cisplatine; drug resistance; nucleotide synthesis; résistance aux médicaments; synthèse des nucléotides