Abstract
The MMAC/PTEN tumor suppressor gene encodes for a phosphatase that recently has been shown to have phosphotidylinositol phosphatase activity, implicating its possible involvement in phosphatidylinositol 3′-kinase-mediated signaling. To investigate possible alterations in growth factor-mediated signal transduction, an adenovirus containing MMAC/PTEN, Ad-MMAC, previously shown to inhibit growth and tumorigenicity in glioma cells, was used to acutely express the transgene. Human glioma cells infected with Ad-MMAC but not with control adenoviruses exhibited an inhibition of phosphorylation of both activating residues of Akt, Ser-473, and Thr-308, along with Akt's serine/threonine kinase activity, without significantly altering Akt expression. The effects of functional MMAC/PTEN expression were relatively specific, because members of several other growth factor-mediated signaling pathways showed no altered responses. The presence of MMAC/PTEN also inhibited phosphorylation of BAD, although no evidence of apoptosis in the in situ treated cells was observed. However, U251 glioma cells infected with Ad-MMAC were induced to undergo anoikis at a significantly higher rate than U251 cells treated with control viruses or mock infected with media. These results demonstrate that the acute administration of MMAC/PTEN results in the inhibition of Akt-mediated signaling, growth inhibition, and anoikis, implying that loss of MMAC/PTEN increases cellular proliferation and significantly augments a cell's survival potential during cellular processes that are associated with malignancy.
Footnotes
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↵1 Supported by NIH Grants CA56041 and CA55261, State of Texas Advanced Technology Program Grant 97-110, and the Pediatric Brain Tumor Foundation (to P. A. S.) and NIH Grant CA71418 (to G. B. M.).
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↵2 The first two authors contributed equally to this work.
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↵3 To whom requests for reprints should be addressed, at Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, Box 316, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: (713) 792-3003; Fax: (713) 745-1183; E-mail: steckpa@audumla.mdacc.tmc.edu.
- Received August 20, 1998.
- Accepted October 16, 1998.
- ©1998 American Association for Cancer Research.