Abstract
The tumor suppressor gene PTEN (MMAC1, TEP1) encodes a dual-specificity phosphatase and is considered a progression-associated target of genetic alterations in human gliomas. Recently, it has been reported that the introduction of wild type PTEN into glioma cells containing endogenous mutant PTEN alleles (U87MG, LN-308), but not in those which retain wild-type PTEN (LN-18, LN-229), causes growth suppression and inhibits cellular migration, spreading and focal adhesion. Here, we show that PTEN gene transfer has no effect on the chemosensitivity of the four cell lines. Further, a correlational analysis of the endogenous PTEN status of 12 human glioma cell lines with their sensitivity to seven different cancer chemotherapy drugs reveals no link between PTEN and chemosensitivity. In contrast, ectopic expression of wild type PTEN, but not the PTENG129R mutant, in PTEN-mutant gliomas markedly sensitizes these cells to irradiation and to CD95-ligand (CD95L)-induced apoptosis. PTEN-mediated facilitation of CD95L-induced apoptosis is associated with enhanced CD95L-evoked caspase 3 activity. Protein kinase B (PKB/Akt), previously shown to inhibit CD95L-induced apoptosis in nonglial COS7 cells, is inactivated by dephosphorylation. Interestingly, both PTEN-mutant U87MG and PTEN-wild-type LN-229 cells contain phosphorylated PKB constitutively. Wild-type PTEN gene transfer promotes dephosphorylation of PKB specifically in U87MG cells but not in LN-229 cells. Sensitization of U87MG cells to CD95L-apoptosis by wild-type PTEN is blocked by insulin-like growth factor-1 (IGF-1). The protection by IGF-1 is inhibited by the phosphoinositide 3-OH (PI 3) kinase inhibitor, wortmannin. Although PKB is a down-stream target of PI 3 kinase, the protection by IGF-1 was not associated with the reconstitution of PKB phosphorylation. Thus, PTEN may sensitize human malignant glioma cells to CD95L-induced apoptosis in a PI 3 kinase-dependent manner that may not require PKB phosphorylation.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Abbreviations
- CD95L:
-
CD95 ligand
- EGF:
-
epidermal growth factor
- IGF-1:
-
insulin-like growth factor-1
- PTEN:
-
pBP-PTEN-HA
- PKB:
-
protein kinase B
- PI (3,4,5)P3:
-
phosphatidylinositol 3,4,5-trisphosphate
- PI(4,5)P2:
-
phosphatidylinositol 4,5-bisphosphate
- PI 3-kinase:
-
phosphoinositide 3-OH kinase
- PDGF:
-
platelet derived growth factor
- PTENG129R-HA:
-
PTENG129R
- (WM):
-
wortmannin
References
Baserga R. . 1995 Cancer Res. 55: 249–252.
Cheney I, Johnson D, Vaillancourt M-T, Avanzini J, Morimoto A, Demers G, Wills K, Shabram P, Bolen J, Tavtigian S and Bookstein R. . 1998 Cancer Res. 58: 2331–2334.
Crowder R and Freeman R. . 1998 J. Neurosci. 18: 2933–2943.
Downward J. . 1998 Curr. Biol. 10: 262–267.
Dudek H, Datta S, Franke T, Birnbaum M, Yao R, Cooper G, Segal R, Kaplan D and Greenberg M. . 1997 Science 275: 661–665.
Duerr E-M, Rollbrocker B, Hayashi Y, Peters N, Meyer-Puttlitz B, Louis D, Schramm J, Wiestler O, Parsons R, Eng C and Deimling v A. . 1998 Oncogene 16: 2259–2264.
Furnari F, Lin H, Huang H-J and Cavenee W. . 1997 Proc. Natl. Acad. Sci. USA 94: 12479–12484.
Häusler P, Papoff G, Eramo A, Reif K, Cantrell D and Ruberti G. . 1998 Eur. J. Immunol. 28: 57–69.
Li D-M and Sun H. . 1997 Cancer Res. 57: 2124–2129.
Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang S, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner S, Giovanella B, Ittmann M, Tycko B, Hibshoosh H, Wigler M and Parsons R. . 1997 Science 275: 1943–1947.
Liu W, James C, Frederick L, Alderete B and Jenkins R. . 1997 Cancer Res. 57: 5254–5257.
Maehama T and Dixon J. . 1998 J. Biol. Chem. 273: 13375–13378.
Marte B and Downward J. . 1997 Trends Biochem. Sci. 22: 355–358.
Myers MP, Stolarov JP, Eng C, Li J, Wang SI, Wigler MH, Parsons R and Tonks NK. . 1997 Proc. Natl. Acad. Sci. USA 94: 9052–9057.
Rhei E, Kang L, Bolomolniy F, Federici M, Borgen P and Boyd J. . 1997 Cancer Res. 57: 3657–3759.
Rieger J, Naumann U, Glaser T, Ashkenazi A and Weller M. . 1998 FEBS Letts 427: 124–128.
Roth W, Fontana A, Trepel M, Dichgans J, Reed JC and Weller M. . 1997 Cancer Immunol. Immunother. 44: 55–63.
Schulz JB, Bremen D, Reed JC, Lommatzsch J, Takayama S, Wüller U, Löschmann P-A, Klockgether T and Weller M. . 1997 J. Neurochem. 69: 2075–2086.
Tamura M, Gu J, Matsumoto K, Aota S-i, Parsons R and Yamada K. . 1998 Science 280: 1614–1617.
Teng D-F, Hu R, Lin H, Davis T, Iliev D, Frye C, Swedlund B, Hansen K, Vinson V, Gumpper K, Ellis L, El-Nagger A, Frazier M, Jasser S, Langford L, Lee J, Mills G, Pershouse M, Pollack R, Tornos C, Troncoso P, Yung W, Fujii G, Berson A, Bookstein R, Bolen J, Tavtigian S and Steck P. . 1997 Cancer Res. 57: 5221–5225.
Wang S, Puc J, Li J, Bruce J, Cairns P, Sidransky D and Parsons R. . 1997 Cancer Res. 57: 4183–4186.
Weller M, Frei K, Groscurth P, Krammer PH and Yonekawa Y. . 1994 J. Clin. Invest. 94: 954–964.
Weller M, Rieger J, Grimmel C, Van Meir E, De Tribolet N, Krajewski S, Reed J, Von Deimling A and Dichgans J. . 1998 Int. J. Cancer 79: 1–5.
Weller M, Trepel M, Grimmel C, Schabet M, Bremen D, Krajewski S and Reed JC. . 1997 Neurol. Res. 19: 459–470.
Acknowledgements
Supported by the German Research Foundation (We 1502/5-2) and the IKFZ Tübingen
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Wick, W., Furnari, F., Naumann, U. et al. PTEN gene transfer in human malignant glioma: sensitization to irradiation and CD95L-induced apoptosis. Oncogene 18, 3936–3943 (1999). https://doi.org/10.1038/sj.onc.1202774
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1202774
Keywords
This article is cited by
-
AEBP1 down regulation induced cell death pathway depends on PTEN status of glioma cells
Scientific Reports (2019)
-
Combining PARP inhibitors with radiation therapy for the treatment of glioblastoma: Is PTEN predictive of response?
Clinical and Translational Oncology (2017)
-
Epigenetics in radiation-induced fibrosis
Oncogene (2015)
-
MicroRNAs involved in the EGFR/PTEN/AKT pathway in gliomas
Journal of Neuro-Oncology (2012)
-
Phospho-ERK and AKT status, but not KRAS mutation status, are associated with outcomes in rectal cancer treated with chemoradiotherapy
Radiation Oncology (2011)