Zoledronic acid inhibits the pentose phosphate pathway through attenuating the Ras‑TAp73‑G6PD axis in bladder cancer cells

Wang,Xiaolin; Wu,Guang; Cao,Guangxin; Yang,Lei; Xu,Haifei; Huang,Jian; Hou,Jianquan

doi:10.3892/mmr.2015.3995

Zoledronic acid inhibits the pentose phosphate pathway through attenuating the Ras‑TAp73‑G6PD axis in bladder cancer cells

Authors:
- Xiaolin Wang
- Guang Wu
- Guangxin Cao
- Lei Yang
- Haifei Xu
- Jian Huang
- Jianquan Hou
View Affiliations

Affiliations: Department of Urology, First Affiliated Hospital, Soochow University, Suzhou, Jiangsu 215006, P.R. China, Department of Urology, First People's Hospital of Wujiang, Suzhou, Jiangsu 215200, P.R. China, Department of Urology, Nantong Tumor Hospital, Nantong, Jiangsu 226361, P.R. China, Department of Medical Oncology, Nantong Tumor Hospital, Nantong, Jiangsu 226361, P.R. China
Published online on: June 24, 2015 https://doi.org/10.3892/mmr.2015.3995
Pages: 4620-4625

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	Parkin DM: The global burden of urinary bladder cancer. Scand J Urol Nephrol. (Suppl): 12–20. 2008. View Article : Google Scholar
2	Noon AP, Albertsen PC, Thomas F, Rosario DJ and Catto JW: Competing mortality in patients diagnosed with bladder cancer: Evidence of undertreatment in the elderly and female patients. Br J Cancer. 108:1534–1540. 2013. View Article : Google Scholar : PubMed/NCBI
3	Zarogoulidis K, Boutsikou E, Zarogoulidis P, Eleftheriadou E, Kontakiotis T, Lithoxopoulou H, Tzanakakis G, Kanakis I and Karamanos NK: The impact of zoledronic acid therapy in survival of lung cancer patients with bone metastasis. Int J Cancer. 125:1705–1709. 2009. View Article : Google Scholar : PubMed/NCBI
4	Hirata H, Hinoda Y, Ueno K, Shahryari V, Tabatabai ZL and Dahiya R: MicroRNA-1826 targets VEGFC, beta-catenin (CTNNB1) and MEK1 (MAP2K1) in human bladder cancer. Carcinogenesis. 33:41–48. 2012. View Article : Google Scholar :
5	Alcaraz A, González-López R, Morote J, de la Piedra C, Meseguer C, Esteban E, Climent M, González-Gragera B, Alvarez-Ossorio JL, Chirivella I, et al: Biochemical markers of bone turnover and clinical outcome in patients with renal cell and bladder carcinoma with bone metastases following treatment with zoledronic acid: The TUGAMO study. Br J Cancer. 109:121–130. 2013. View Article : Google Scholar : PubMed/NCBI
6	Zaghloul MS, Boutrus R, El-Hossieny H, Kader YA, El-Attar I and Nazmy M: A prospective, randomized, placebo-controlled trial of zoledronic acid in bony metastatic bladder cancer. Int J Clin Oncol. 15:382–389. 2010. View Article : Google Scholar : PubMed/NCBI
7	Saad F and Eastham JA: Zoledronic acid use in patients with bone metastases from renal cell carcinoma or bladder cancer. Semin Oncol. 37(Suppl 1): S38–S44. 2010. View Article : Google Scholar : PubMed/NCBI
8	Gouin F, Ory B, Rédini F and Heymann D: Zoledronic acid slows down rat primary chondrosarcoma development, recurrent tumor progression after intralesional curretage and increases overall survival. Int J Cancer. 119:980–984. 2006. View Article : Google Scholar : PubMed/NCBI
9	Goffinet M, Thoulouzan M, Pradines A, Lajoie-Mazenc I, Weinbaum C, Faye JC and Séronie-Vivien S: Zoledronic acid treatment impairs protein geranyl-geranylation for biological effects in prostatic cells. BMC Cancer. 6:602006. View Article : Google Scholar : PubMed/NCBI
10	Koto K, Murata H, Kimura S, Sawai Y, Horie N, Matsui T, Ryu K, Ashihara E, Maekawa T, Kubo T, et al: Zoledronic acid significantly enhances radiation-induced apoptosis against human fibrosarcoma cells by inhibiting radioadaptive signaling. Int J Oncol. 42:525–534. 2013.
11	Rowinsky EK, Windle JJ and Von Hoff DD: Ras protein farne-syltransferase: A strategic target for anticancer therapeutic development. J Clin Oncol. 17:3631–3652. 1999.PubMed/NCBI
12	Wei J, Zaika E and Zaika A: p53 Family: Role of protein isoforms in human cancer. J Nucleic Acids. 2012:6873592012. View Article : Google Scholar
13	Stiewe T and Putzer BM: Role of p73 in malignancy: Tumor suppressor or oncogene? Cell Death Differ. 9:237–245. 2002. View Article : Google Scholar : PubMed/NCBI
14	Lunghi P, Costanzo A, Mazzera L, Rizzoli V, Levrero M and Bonati A: The p53 family protein p73 provides new insights into cancer chemosensitivity and targeting. Clin Cancer Res. 15:6495–6502. 2009. View Article : Google Scholar : PubMed/NCBI
15	Tomkova K, Belkhiri A, El-Rifai W and Zaika AI: p73 isoforms can induce T-cell factor-dependent transcription in gastrointestinal cells. Cancer Res. 64:6390–6393. 2004. View Article : Google Scholar : PubMed/NCBI
16	Zaika AI and El-Rifai W: The role of p53 protein family in gastrointestinal malignancies. Cell Death Differ. 13:935–940. 2006. View Article : Google Scholar : PubMed/NCBI
17	Conforti F, Yang AL, Agostini M, Rufini A, Tucci P, Nicklison-Chirou MV, Grespi F, Velletri T, Knight RA, Melino G, et al: Relative expression of TAp73 and ΔNp73 isoforms. Aging (Albany NY). 4:202–205. 2012.
18	Rufini A, Agostini M, Grespi F, Tomasini R, Sayan BS, Niklison-Chirou MV, Conforti F, Velletri T, Mastino A, Mak TW, et al: p73 in Cancer. Genes Cancer. 2:491–502. 2011. View Article : Google Scholar : PubMed/NCBI
19	Lin D, Cui Z, Kong L, Cheng F, Xu J and Lan F: p73 participates in WWOX-mediated apoptosis in leukemia cells. Int J Mol Med. 31:849–854. 2013.PubMed/NCBI
20	Grob TJ, Novak U, Maisse C, Barcaroli D, Lüthi AU, Pirnia F, Hügli B, Graber HU, De Laurenzi V, Fey MF, et al: Human delta Np73 regulates a dominant negative feedback loop for TAp73 and p53. Cell Death Differ. 8:1213–1223. 2001. View Article : Google Scholar : PubMed/NCBI
21	Samudio I, Fiegl M and Andreeff M: Mitochondrial uncoupling and the Warburg effect: Molecular basis for the reprogramming of cancer cell metabolism. Cancer Res. 69:2163–2166. 2009. View Article : Google Scholar : PubMed/NCBI
22	Cairns RA, Harris IS and Mak TW: Regulation of cancer cell metabolism. Nat Rev Cancer. 11:85–95. 2011. View Article : Google Scholar : PubMed/NCBI
23	Jones RG and Thompson CB: Tumor suppressors and cell metabolism: A recipe for cancer growth. Genes Dev. 23:537–548. 2009. View Article : Google Scholar : PubMed/NCBI
24	Jiang P, Du W, Wang X, Mancuso A, Gao X, Wu M and Yang X: p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nat Cell Biol. 13:310–316. 2011. View Article : Google Scholar : PubMed/NCBI
25	Du W, Jiang P, Mancuso A, Stonestrom A, Brewer MD, Minn AJ, Mak TW, Wu M and Yang X: TAp73 enhances the pentose phosphate pathway and supports cell proliferation. Nat Cell Biol. 15:991–1000. 2013. View Article : Google Scholar : PubMed/NCBI
26	Fernandez-Garcia B, Vaqué JP, Herreros-Villanueva M, Marques-Garcia F, Castrillo F, Fernandez-Medarde A, León J and Marín MC: p73 cooperates with Ras in the activation of MAP kinase signaling cascade. Cell Death Differ. 14:254–265. 2007. View Article : Google Scholar
27	Chang J, Wang W, Zhang H, Hu Y and Yin Z: Bisphosphonates regulate cell proliferation, apoptosis and pro-osteoclastic expression in MG-63 human osteosarcoma cells. Oncol Lett. 4:299–304. 2012.PubMed/NCBI
28	Ohtsuka Y, Manabe A, Kawasaki H, Hasegawa D, Zaike Y, Watanabe S, Tanizawa T, Nakahata T and Tsuji K: RAS-blocking bisphosphonate zoledronic acid inhibits the abnormal proliferation and differentiation of juvenile myelomonocytic leukemia cells in vitro. Blood. 106:3134–3141. 2005. View Article : Google Scholar : PubMed/NCBI
29	Riganti C, Castella B, Kopecka J, Campia I, Coscia M, Pescarmona G, Bosia A, Ghigo D and Massaia M: Zoledronic acid restores doxorubicin chemosensitivity and immunogenic cell death in multidrug-resistant human cancer cells. PLoS One. 8:e609752013. View Article : Google Scholar : PubMed/NCBI
30	Cairns RA, Harris I, McCracken S and Mak TW: Cancer cell metabolism. Cold Spring Harb Symp Quant Biol. 76:299–311. 2011. View Article : Google Scholar : PubMed/NCBI