Interferon-gamma-induced dephosphorylation of STAT3 and apoptosis are dependent on the mTOR pathway

Peng Fang, Vivian Hwa, Ronald (Ron) Rosenfeld

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Interferon-gamma (IFN-γ) exhibits diverse biological activities, including control of cell growth and tumor suppression. Here, we report that the treatment of M12 cells, a human metastatic prostate cancer cell line, with IFN-γ, resulted in marked inhibition of cell proliferation and induced apoptosis. These effects were not seen with either IFN-α or IFN-β. M12 cells, like many other human cancer cells, contain constitutively activated signal transducer and activator of transcription 3 (STAT3). The basal levels of both Akt and ERK1/2 phosphorylation are also markedly elevated in M12 cells. Strikingly, IFN-γ-induced apoptosis and growth inhibition of M12 cells were associated with persistent suppression of the constitutive tyrosine-phosphorylated STAT3 (pY-STAT3). The IFN-γ-induced dephosphorylation of pY-STAT3, however, was inhibited when the mTOR pathway was specifically blocked by rapamycin. Inhibition of PI-3K with low-dose LY294002, or MAPK with PD98059 also suppressed the mTOR/p70 S6k pathway, and correlated with the blockage of IFN-γ-induced dephosphorylation of pY-STAT3. Simultaneously, treatment with LY294002, PD98059, or rapamycin abolished IFN-γ-induced apoptosis in M12 cells. The inhibition of the mTOR pathway, however, did not affect IFN-γ-induced activation of STAT1 pathway, and suppression of STAT1 expression by siRNA had no effect on IFN-γ-induced dephosphorylation of pY-STAT3. Taken together, these results demonstrate that an intact mTOR pathway is critical for IFN-γ-induced suppression of pY-STAT3 and apoptosis. Our study thus provides novel insights into the contributions of signaling pathways other than the classical JAK/STAT1 pathway in the anti-proliferative, proapoptotic actions of IFN-γ.

Original languageEnglish (US)
Pages (from-to)1229-1239
Number of pages11
JournalExperimental Cell Research
Volume312
Issue number8
DOIs
StatePublished - May 1 2006

Fingerprint

STAT3 Transcription Factor
Interferon-gamma
Apoptosis
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Sirolimus
Critical Pathways
Growth
Phosphatidylinositol 3-Kinases
Small Interfering RNA
Tyrosine
Neoplasms
Prostatic Neoplasms

Keywords

  • Apoptosis
  • Interferon-gamma
  • mTOR
  • STAT1
  • STAT3

ASJC Scopus subject areas

  • Cell Biology

Cite this

Interferon-gamma-induced dephosphorylation of STAT3 and apoptosis are dependent on the mTOR pathway. / Fang, Peng; Hwa, Vivian; Rosenfeld, Ronald (Ron).

In: Experimental Cell Research, Vol. 312, No. 8, 01.05.2006, p. 1229-1239.

Research output: Contribution to journalArticle

Fang, Peng ; Hwa, Vivian ; Rosenfeld, Ronald (Ron). / Interferon-gamma-induced dephosphorylation of STAT3 and apoptosis are dependent on the mTOR pathway. In: Experimental Cell Research. 2006 ; Vol. 312, No. 8. pp. 1229-1239.
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