Abstract
The PTEN tumor suppressor is frequently mutated in human tumors. Loss of PTEN function is associated with constitutive survival signaling through the phosphatidylinositol-3 kinase/Akt pathway. Therefore, we asked if reconstitution of PTEN function would lead to the reversal of resistance to apoptosis in prostate cancer cells. Adenovirus-mediated expression of PTEN completely suppressed constitutive Akt activation in LNCaP prostate cancer cells and enhanced apoptosis induced by a broad range of apoptotic stimuli. PTEN expression sensitized cells to death receptor-mediated apoptosis induced by tumor necrosis factor, anti-Fas antibody, and TRAIL. PTEN also sensitized cells to non-receptor mediated apoptosis induced by a kinase inhibitor staurosporine and chemotherapeutic agents mitoxantrone and etoposide. PTEN-mediated apoptosis was accompanied by caspase-3 and caspase-8 activation and was inhibited by a broad specificity caspase inhibitor Z-VAD-fmk. Bcl-2 overexpression also blocked PTEN-mediated apoptosis. Lipid phosphatase activity of PTEN is required for apoptosis as the PTEN G129E mutant selectively deficient in lipid phosphatase activity was unable to sensitize cells to apoptosis. PTEN-mediated apoptosis involves a FADD-dependent pathway for both death receptor-mediated and drug-induced apoptosis as coexpression of a dominant negative FADD mutant blocked PTEN-mediated apoptosis. Since in death receptor signaling, FADD mediates activation of caspase-8, which in turn cleaves BID, and since caspase-8 is activated in PTEN-mediated apoptosis, we examined BID cleavage in PTEN-mediated apoptosis. PTEN facilitated BID cleavage after treatment with low doses of staurosporine and mitoxantrone. BID cleavage was inhibited by dominant negative FADD. Taken together, these data are consistent with the hypothesis that PTEN promotes drug-induced apoptosis by facilitating caspase-8 activation and BID cleavage through a FADD-dependent pathway.
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
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Ashkenazi A, Dixit VM . 1999 Curr. Opin. Cell. Biol. 11: 255–260
Bradham CA, Qian T, Streetz K, Trautwein C, Brenner DA, Lemasters JJ . 1998 Mol. Cell. Biol. 18: 6353–6364
Budihardjo I, Oliver H, Lutter M, Luo X, Wang X . 1999 Annu. Rev. Cell. Dev. Biol. 15: 269–290
Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC . 1998 Science 282: 1318–1321
Chinnaiyan AM, Tepper CG, Seldin MF, O'Rourke K, Kischkel FC, Hellbardt S, Krammer PH, Peter ME, Dixit VM . 1996 J. Biol. Chem. 271: 4961–4965
Choi KB, Wong F, Harlan JM, Chaudhary PM, Hood L, Karsan A . 1998 J. Biol. Chem. 273: 20185–20188
Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME . 1997 Cell 91: 231–241
Davies MA, Koul D, Dhesi H, Berman R, McDonnell TJ, McConkey D, Yung WK, Steck PA . 1999 Cancer Res. 59: 2551–2556
del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G . 1997 Science 278: 687–689
Di Cristofano A, Pesce B, Cordon-Cardo C, Pandolfi PP . 1998 Nat. Genet. 19: 348–355
Eskes R, Desagher S, Antonsson B, Martinou JC . 2000 Mol. Cell. Biol. 20: 929–935
Frisch SM . 1999 Curr. Biol. 9: 1047–1049
Gomez-Foix AM, Coats WS, Baque S, Alam T, Gerard RD, Newgard CB . 1992 J. Biol. Chem. 267: 25129–25134
Han Z, Pantazis P, Wyche JH, Kouttab N, Kidd VJ, Hendrickson EA . 2001 J. Biol. Chem. 276: 38748–38754
He TC, Zhou S, da Costa LT, Yu J, Kinzler KW, Vogelstein B . 1998 Proc. Natl. Acad. Sci. USA 95: 2509–2514
Hlobilkova A, Guldberg P, Thullberg M, Zeuthen J, Lukas J, Bartek J . 2000 Exp. Cell. Res. 256: 571–577
Klein KA, Reiter RE, Redula J, Moradi H, Zhu XL, Brothman AR, Lamb DJ, Marcelli M, Belldegrun A, Witte ON, Sawyers CL . 1997 Nat. Med. 3: 402–408
Kulik G, Carson JP, Vomastek T, Overman K, Gooch BD, Srinivasula S, Alnemri E, Nunez G, Weber MJ . 2001 Cancer Res. 61: 2713–2719
Li H, Zhu H, Xu CJ, Yuan J . 1998 Cell 94: 491–501
Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R . 1997a Science 275: 1943–1947
Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X . 1997b Cell 91: 479–489
Luo X, Budihardjo I, Zou H, Slaughter C, Wang X . 1998 Cell 94: 481–490
Madrid LV, Wang CY, Guttridge DC, Schottelius AJ, Baldwin Jr AS, Mayo MW . 2000 Mol. Cell. Biol. 20: 1626–1638
Maehama T, Dixon JE . 1998 J. Biol. Chem. 273: 13375–13378
Maier D, Jones G, Li X, Schonthal AH, Gratzl O, Van Meir EG, Merlo A . 1999 Cancer Res. 59: 5479–5482
Marcelli M, Cunningham GR, Walkup M, He Z, Sturgis L, Kagan C, Mannucci R, Nicoletti I, Teng B, Denner L . 1999 Cancer Res. 59: 382–390
McMenamin ME, Soung P, Perera S, Kaplan I, Loda M, Sellers WR . 1999 Cancer Res. 59: 4291–4296
Micheau O, Solary E, Hammann A, Dimanche-Boitrel MT . 1999 J. Biol. Chem. 274: 7987–7992
Myers MP, Pass I, Batty IH, Van der Kaay J, Stolarov JP, Hemmings BA, Wigler MH, Downes CP, Tonks NK . 1998 Proc. Natl. Acad. Sci. USA 95: 13513–13518
Myers MP, Stolarov JP, Eng C, Li J, Wang SI, Wigler MH, Parsons R, Tonks NK . 1997 Proc. Natl. Acad. Sci. USA 94: 9052–9057
Nesterov A, Lu X, Johnson M, Miller GJ, Ivashchenko Y, Kraft AS . 2001 J. Biol. Chem. 276: 10767–10774
Newton K, Harris AW, Bath ML, Smith KG, Strasser A . 1998 EMBO J. 17: 706–718
Podsypanina K, Ellenson LH, Nemes A, Gu J, Tamura M, Yamada KM, Cordon-Cardo C, Catoretti G, Fisher PE, Parsons R . 1999 Proc. Natl. Acad. Sci. USA 96: 1563–1568
Raffo AJ, Perlman H, Chen MW, Day ML, Streitman JS, Buttyan R . 1995 Cancer Res. 55: 4438–4445
Rytomaa M, Martins LM, Downward J . 1999 Curr. Biol. 9: 1043–1046
Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, Krammer PH, Peter ME . 1998 EMBO J. 17: 1675–1687
Scaffidi C, Medema JP, Krammer PH, Peter ME . 1997 J. Biol. Chem. 272: 26953–26958
Shao RG, Cao CX, Nieves-Neira W, Dimanche-Boitrel MT, Solary E, Pommier Y . 2001 Oncogene 20: 1852–1859
Sizemore N, Leung S, Stark GR . 1999 Mol. Cell. Biol. 19: 4798–4805
Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, Ruland J, Penninger JM, Siderovski DP, Mak TW . 1998 Cell 95: 29–39
Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DH, Tavtigian SV . 1997 Nat. Genet. 15: 356–362
Suzuki A, de la Pompa JL, Stambolic V, Elia AJ, Sasaki T, del Barco Barrantes I, Ho A, Wakeham A, Itie A, Khoo W, Fukumoto M, Mak TW . 1998a Curr. Biol. 8: 1169–1178
Suzuki H, Freije D, Nusskern DR, Okami K, Cairns P, Sidransky D, Isaacs WB, Bova GS . 1998b Cancer Res. 58: 204–209
Tang D, Lahti JM, Grenet J, Kidd VJ . 1999 J. Biol. Chem. 274: 7245–7252
Thakkar H, Chen X, Tyan F, Gim S, Robinson H, Lee C, Pandey SK, Nwokorie C, Onwudiwe N, Srivastava RK . 2001 J. Biol. Chem. 276: 38361–38369
Wang CY, Mayo MW, Baldwin Jr AS . 1996 Science 274: 784–787
Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M, Thompson CB, Korsmeyer SJ . 2000 Genes Dev. 14: 2060–2071
Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB, Korsmeyer SJ . 2001 Science 292: 727–730
Weng LP, Brown JL, Eng C . 2001 Hum. Mol. Genet. 10: 599–604
Whang YE, Wu X, Suzuki H, Reiter RE, Tran C, Vessella RL, Said JW, Isaacs WB, Sawyers CL . 1998 Proc. Natl. Acad. Sci. USA 95: 5246–5250
Wu X, Senechal K, Neshat MS, Whang YE, Sawyers CL . 1998 Proc. Natl. Acad. Sci. USA 95: 15587–15591
Yeh WC, Pompa JL, McCurrach ME, Shu HB, Elia AJ, Shahinian A, Ng M, Wakeham A, Khoo W, Mitchell K, El-Deiry WS, Lowe SW, Goeddel DV, Mak TW . 1998 Science 279: 1954–1958
Acknowledgements
This work was supported by grants from the Department of Defense Prostate Cancer Research Program (DAMD17-00-1-0037) and NIH (CA85772). We thank Ralph Buttyan, Marco Marcelli, Lily Wu, David Brenner, Peter Krammer and Charles Sawyers for reagents, and Marty Mayo, Al Baldwin, Chris Gregory and Charles Sawyers for discussions and reviewing the manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Yuan, XJ., Whang, Y. PTEN sensitizes prostate cancer cells to death receptor-mediated and drug-induced apoptosis through a FADD-dependent pathway. Oncogene 21, 319–327 (2002). https://doi.org/10.1038/sj.onc.1205054
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1205054
Keywords
This article is cited by
-
Transient stabilization, rather than inhibition, of MYC amplifies extrinsic apoptosis and therapeutic responses in refractory B-cell lymphoma
Leukemia (2019)
-
Basement membrane extract attenuates the more malignant gene expression profile accentuated by fibronectin in prostate cancer cells
Molecular and Cellular Biochemistry (2019)
-
The impact of phosphatases on proliferative and survival signaling in cancer
Cellular and Molecular Life Sciences (2018)
-
The oncogenic microRNA miR-21 promotes regulated necrosis in mice
Nature Communications (2015)
-
The challenge of pancreatic cancer therapy and novel treatment strategy using engineered mesenchymal stem cells
Cancer Gene Therapy (2014)