Inositol Pyrophosphates Promote Tumor Growth and Metastasis by Antagonizing Liver Kinase B1

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2015 Jan 25

PMID 25617365

Citations 55

Authors

Feng Rao

Jing Xu

Chenglai Fu

Jiyoung Y Cha

Moataz M Gadalla

Risheng Xu

James C Barrow

Solomon H Snyder

Affiliations

Soon will be listed here.

Abstract

The inositol pyrophosphates, molecular messengers containing an energetic pyrophosphate bond, impact a wide range of biologic processes. They are generated primarily by a family of three inositol hexakisphosphate kinases (IP6Ks), the principal product of which is diphosphoinositol pentakisphosphate (IP7). We report that IP6K2, via IP7 synthesis, is a major mediator of cancer cell migration and tumor metastasis in cell culture and in intact mice. IP6K2 acts by enhancing cell-matrix adhesion and decreasing cell-cell adhesion. This action is mediated by IP7-elicited nuclear sequestration and inactivation of the tumor suppressor liver kinase B1 (LKB1). Accordingly, inhibitors of IP6K2 offer promise in cancer therapy.

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References

Saiardi A, Nagata E, Luo H, Snowman A, Snyder S . Identification and characterization of a novel inositol hexakisphosphate kinase. J Biol Chem. 2001; 276(42):39179-85. DOI: 10.1074/jbc.M106842200. View

Aoki M, Sobek V, Maslyar D, Hecht A, Vogt P . Oncogenic transformation by beta-catenin: deletion analysis and characterization of selected target genes. Oncogene. 2002; 21(46):6983-91. DOI: 10.1038/sj.onc.1205796. View

Ewan K, Henshall-Powell R, Ravani S, Pajares M, Arteaga C, Warters R . Transforming growth factor-beta1 mediates cellular response to DNA damage in situ. Cancer Res. 2002; 62(20):5627-31. View

Baas A, Boudeau J, Sapkota G, Smit L, Medema R, Morrice N . Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD. EMBO J. 2003; 22(12):3062-72. PMC: 162144. DOI: 10.1093/emboj/cdg292. View

Lizcano J, Goransson O, Toth R, Deak M, Morrice N, Boudeau J . LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J. 2004; 23(4):833-43. PMC: 381014. DOI: 10.1038/sj.emboj.7600110. View

Moser A, Pitot H, Dove W . A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science. 1990; 247(4940):322-4. DOI: 10.1126/science.2296722. View

Mitra S, Hanson D, Schlaepfer D . Focal adhesion kinase: in command and control of cell motility. Nat Rev Mol Cell Biol. 2005; 6(1):56-68. DOI: 10.1038/nrm1549. View

Alessi D, Sakamoto K, Bayascas J . LKB1-dependent signaling pathways. Annu Rev Biochem. 2006; 75:137-63. DOI: 10.1146/annurev.biochem.75.103004.142702. View

Mulugu S, Bai W, Fridy P, Bastidas R, Otto J, Dollins D . A conserved family of enzymes that phosphorylate inositol hexakisphosphate. Science. 2007; 316(5821):106-9. DOI: 10.1126/science.1139099. View

10.

Illies C, Gromada J, Fiume R, Leibiger B, Yu J, Juhl K . Requirement of inositol pyrophosphates for full exocytotic capacity in pancreatic beta cells. Science. 2007; 318(5854):1299-302. DOI: 10.1126/science.1146824. View

11.

Song P, Xie Z, Wu Y, Xu J, Dong Y, Zou M . Protein kinase Czeta-dependent LKB1 serine 428 phosphorylation increases LKB1 nucleus export and apoptosis in endothelial cells. J Biol Chem. 2008; 283(18):12446-55. PMC: 2431011. DOI: 10.1074/jbc.M708208200. View

12.

Rajput A, San Martin I, Rose R, Beko A, LeVea C, Sharratt E . Characterization of HCT116 human colon cancer cells in an orthotopic model. J Surg Res. 2007; 147(2):276-81. DOI: 10.1016/j.jss.2007.04.021. View

13.

Kim S, Kim S, Maag D, Maxwell M, Resnick A, Juluri K . Amino acid signaling to mTOR mediated by inositol polyphosphate multikinase. Cell Metab. 2011; 13(2):215-21. PMC: 3042716. DOI: 10.1016/j.cmet.2011.01.007. View

14.

Cavallaro U, Dejana E . Adhesion molecule signalling: not always a sticky business. Nat Rev Mol Cell Biol. 2011; 12(3):189-97. DOI: 10.1038/nrm3068. View

15.

Chakraborty A, Kim S, Snyder S . Inositol pyrophosphates as mammalian cell signals. Sci Signal. 2011; 4(188):re1. PMC: 3667551. DOI: 10.1126/scisignal.2001958. View

16.

Szijgyarto Z, Garedew A, Azevedo C, Saiardi A . Influence of inositol pyrophosphates on cellular energy dynamics. Science. 2011; 334(6057):802-5. DOI: 10.1126/science.1211908. View

17.

Eneling K, Brion L, Pinto V, Pinho M, Sznajder J, Mochizuki N . Salt-inducible kinase 1 regulates E-cadherin expression and intercellular junction stability. FASEB J. 2012; 26(8):3230-9. PMC: 3405263. DOI: 10.1096/fj.12-205609. View

18.

Zhang Q, Petrey D, Deng L, Qiang L, Shi Y, Aye Thu C . Structure-based prediction of protein-protein interactions on a genome-wide scale. Nature. 2012; 490(7421):556-60. PMC: 3482288. DOI: 10.1038/nature11503. View

19.

Jadav R, Chanduri M, Sengupta S, Bhandari R . Inositol pyrophosphate synthesis by inositol hexakisphosphate kinase 1 is required for homologous recombination repair. J Biol Chem. 2012; 288(5):3312-21. PMC: 3561551. DOI: 10.1074/jbc.M112.396556. View

20.

Wang H, Wang H, Zhou B, Li C, Zhang F, Wang X . Epithelial-mesenchymal transition (EMT) induced by TNF-α requires AKT/GSK-3β-mediated stabilization of snail in colorectal cancer. PLoS One. 2013; 8(2):e56664. PMC: 3576347. DOI: 10.1371/journal.pone.0056664. View