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

Journal Article · Mon May 01 04:00:00 EDT 2006 · Experimental Cell Research

DOI:https://doi.org/10.1016/j.yexcr.2005.12.011· OSTI ID:20775364

Peng, Fang ^[1]; Hwa, Vivian ^[2]; Rosenfeld, Ron G ^[1]

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1. Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239-3098 (United States)
2. Lucile Packard Foundation for Children's Health, Palo Alto, CA 94304 (United States)

Interferon-gamma (IFN-{gamma}) 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-{gamma}, resulted in marked inhibition of cell proliferation and induced apoptosis. These effects were not seen with either IFN-{alpha} or IFN-{beta}. 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-{gamma}-induced apoptosis and growth inhibition of M12 cells were associated with persistent suppression of the constitutive tyrosine-phosphorylated STAT3 (pY-STAT3). The IFN-{gamma}-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-{gamma}-induced dephosphorylation of pY-STAT3. Simultaneously, treatment with LY294002, PD98059, or rapamycin abolished IFN-{gamma}-induced apoptosis in M12 cells. The inhibition of the mTOR pathway, however, did not affect IFN-{gamma}-induced activation of STAT1 pathway, and suppression of STAT1 expression by siRNA had no effect on IFN-{gamma}-induced dephosphorylation of pY-STAT3. Taken together, these results demonstrate that an intact mTOR pathway is critical for IFN-{gamma}-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-{gamma}.

• OSTI ID: 20775364
• Journal Information: Experimental Cell Research, Journal Name: Experimental Cell Research Journal Issue: 8 Vol. 312; ISSN 0014-4827; ISSN ECREAL
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
APOPTOSIS
CELL PROLIFERATION
INHIBITION
INTERFERON
METASTASES
NEOPLASMS
PHOSPHORYLATION
PHOSPHOTRANSFERASES
PROSTATE
RNA
TRANSCRIPTION
TRANSDUCERS
TYROSINE