PI3K Signaling in Glioma--animal Models and Therapeutic Challenges

Overview

Journal Brain Pathol

Date 2008 Dec 17

PMID 19076776

Citations 75

Authors

Christine K Cheng

Qi-Wen Fan

William A Weiss

Affiliations

Soon will be listed here.

Abstract

The PI3 kinase (PI3K) family plays a complex role in cell biology and metabolism. Signaling through the PI3Ks is frequently activated in many human cancers, including glioblastoma, because of gain-of-function mutations in PIK3CA or loss of PTEN. Experiments involving genetic mouse models and small molecule inhibitors have helped to elucidate the roles of the regulatory and catalytic subunits of PI3K in metabolism and cancer. Downstream of PI3K is Akt, a critical effector of growth, proliferation and survival. The suggested dependence of glioblastoma tumors on PI3K signaling implies that PI3K inhibitors should lead to effective killing of these cancer cells, but that has been shown not to be the case. The engagement of other survival pathways in response to PI3K inhibition prompts the need to develop combination therapies that promote cytotoxicity in cancer cells.

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References

Shaw R, Cantley L . Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature. 2006; 441(7092):424-30. DOI: 10.1038/nature04869. View

Hippert M, OToole P, Thorburn A . Autophagy in cancer: good, bad, or both?. Cancer Res. 2006; 66(19):9349-51. DOI: 10.1158/0008-5472.CAN-06-1597. View

Grahame Hardie D . Minireview: the AMP-activated protein kinase cascade: the key sensor of cellular energy status. Endocrinology. 2003; 144(12):5179-83. DOI: 10.1210/en.2003-0982. View

Yu J, Zhang Y, McIlroy J, Orr G, Backer J . Regulation of the p85/p110 phosphatidylinositol 3'-kinase: stabilization and inhibition of the p110alpha catalytic subunit by the p85 regulatory subunit. Mol Cell Biol. 1998; 18(3):1379-87. PMC: 108851. DOI: 10.1128/MCB.18.3.1379. View

Ciraolo E, Iezzi M, Marone R, Marengo S, Curcio C, Costa C . Phosphoinositide 3-kinase p110beta activity: key role in metabolism and mammary gland cancer but not development. Sci Signal. 2008; 1(36):ra3. PMC: 2694958. DOI: 10.1126/scisignal.1161577. View

Fan Q, Weiss W . Isoform specific inhibitors of PI3 kinase in glioma. Cell Cycle. 2006; 5(20):2301-5. DOI: 10.4161/cc.5.20.3362. View

Prevo R, Deutsch E, Sampson O, Diplexcito J, Cengel K, Harper J . Class I PI3 kinase inhibition by the pyridinylfuranopyrimidine inhibitor PI-103 enhances tumor radiosensitivity. Cancer Res. 2008; 68(14):5915-23. DOI: 10.1158/0008-5472.CAN-08-0757. View

Bi L, Okabe I, Bernard D, Wynshaw-Boris A, Nussbaum R . Proliferative defect and embryonic lethality in mice homozygous for a deletion in the p110alpha subunit of phosphoinositide 3-kinase. J Biol Chem. 1999; 274(16):10963-8. DOI: 10.1074/jbc.274.16.10963. View

Wang S, Puc J, Li J, Bruce J, Cairns P, Sidransky D . Somatic mutations of PTEN in glioblastoma multiforme. Cancer Res. 1997; 57(19):4183-6. View

10.

Luo J, Cantley L . The negative regulation of phosphoinositide 3-kinase signaling by p85 and it's implication in cancer. Cell Cycle. 2005; 4(10):1309-12. DOI: 10.4161/cc.4.10.2062. View

11.

Weinstein I . Cancer. Addiction to oncogenes--the Achilles heal of cancer. Science. 2002; 297(5578):63-4. DOI: 10.1126/science.1073096. View

12.

Kaplan D, Whitman M, Schaffhausen B, Pallas D, White M, Cantley L . Common elements in growth factor stimulation and oncogenic transformation: 85 kd phosphoprotein and phosphatidylinositol kinase activity. Cell. 1987; 50(7):1021-9. DOI: 10.1016/0092-8674(87)90168-1. View

13.

Haas-Kogan D, Prados M, Tihan T, Eberhard D, Jelluma N, Arvold N . Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib. J Natl Cancer Inst. 2005; 97(12):880-7. DOI: 10.1093/jnci/dji161. View

14.

Mueller W, Mizoguchi M, Silen E, Damore K, Nutt C, Louis D . Mutations of the PIK3CA gene are rare in human glioblastoma. Acta Neuropathol. 2005; 109(6):654-5. DOI: 10.1007/s00401-005-1001-0. View

15.

Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang S . PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997; 275(5308):1943-7. DOI: 10.1126/science.275.5308.1943. View

16.

Hingorani S, Tuveson D . Targeting oncogene dependence and resistance. Cancer Cell. 2003; 3(5):414-7. DOI: 10.1016/s1535-6108(03)00115-6. View

17.

Graupera M, Guillermet-Guibert J, Foukas L, Phng L, Cain R, Salpekar A . Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration. Nature. 2008; 453(7195):662-6. DOI: 10.1038/nature06892. View

18.

Li P, Nijhawan D, Budihardjo I, Srinivasula S, Ahmad M, Alnemri E . Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997; 91(4):479-89. DOI: 10.1016/s0092-8674(00)80434-1. View

19.

Elstrom R, Bauer D, Buzzai M, Karnauskas R, Harris M, Plas D . Akt stimulates aerobic glycolysis in cancer cells. Cancer Res. 2004; 64(11):3892-9. DOI: 10.1158/0008-5472.CAN-03-2904. View

20.

Chen J, Zhou L, Entin-Meer M, Yang X, Donker M, Knight Z . Characterization of structurally distinct, isoform-selective phosphoinositide 3'-kinase inhibitors in combination with radiation in the treatment of glioblastoma. Mol Cancer Ther. 2008; 7(4):841-50. DOI: 10.1158/1535-7163.MCT-07-0393. View