title: Zoledronic acid inhibits the pentose phosphate pathway through attenuating the Ras-TAp73-G6PD axis in bladder cancer cells.
abstract: Zoledronic acid (ZA) is the current standard of care for the therapy of patients with bone metastasis or osteoporosis. ZA inhibits the prenylation of small guanosine‑5'-triphosphate (GTP)‑binding proteins, such as Ras, and thus inhibit Ras signaling. The present study demonstrated that ZA inhibited cell proliferation and the pentose phosphate pathway (PPP) in bladder cancer cells. In addition, the expression of glucose‑6‑phosphate dehydrogenase (G6PD, the rate‑limiting enzyme of the PPP) was found to be inhibited by ZA. Furthermore, the stability of TAp73, which activates the expression G6PD was decreased in zoledronic acid treated cells. Decreased levels of Ras‑GTP and phosphorylated‑extracellular signal-regulated kinase 1/2 were also observed following treatment with ZA. This may be due to the fact that activated Ras was reported to stabilize TAp73 inducing its accumulation. The inhibition of Ras activity by PT inhibitor II also significantly reduced the levels of TAp73 and G6PD and the PPP flux. Moreover, knockdown of TAp73, attenuated the PPP flux and eliminated the affection of ZA on the PPP flux. In conclusion, it was proposed that ZA can inhibit stability of TAp73 and attenuate the PPP via blocking Ras signaling in bladder cancer cells.
authors.affiliation: Department of Urology, First Affiliated Hospital, Soochow University, Suzhou, Jiangsu 215006, P.R. China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Urology, First People's Hospital of Wujiang, Suzhou, Jiangsu 215200, P.R. China.
authors.forename: Guang
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Urology, Nantong Tumor Hospital, Nantong, Jiangsu 226361, P.R. China.
authors.forename: Guangxin
authors.initials: G
authors.lastname: Cao
authors.affiliation: Department of Medical Oncology, Nantong Tumor Hospital, Nantong, Jiangsu 226361, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Urology, Nantong Tumor Hospital, Nantong, Jiangsu 226361, P.R. China.
authors.forename: Haifei
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Urology, Nantong Tumor Hospital, Nantong, Jiangsu 226361, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Urology, First Affiliated Hospital, Soochow University, Suzhou, Jiangsu 215006, P.R. China.
authors.forename: Jianquan
authors.initials: J
authors.lastname: Hou
mesh_terms: D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D005954:Glucosephosphate Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009928:Organ Specificity; D010427:Pentose Phosphate Pathway / Q000187:drug effects; D055550:Protein Stability; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000077211:Zoledronic Acid; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D050071:Bone Density Conservation Agents; D004268:DNA-Binding Proteins; D004164:Diphosphonates; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D000077211:Zoledronic Acid; D005954:Glucosephosphate Dehydrogenase; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D018631:ras Proteins