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Activation of STAT1 By IFN-γ Inhibits Growth of Human Non-Small Cell Lung Cancer Cells
October 2004, Vol 126, No. 4_MeetingAbstracts Abstract: Poster Presentations | October 2004
Activation of STAT1 By IFN-γ Inhibits Growth of Human Non-Small Cell Lung Cancer Cells Nikhat Salamat, MD*; Steve A. Maxwell, PhD; J. R. Brewer, BS; Jonathan N. Day, BS; Richard E. Winn, MD; George W. Booz, PhD Scott and White Hospital, Temple, TX Chest Chest. 2004;126(4_MeetingAbstracts):914S. doi:10.1378/chest.126.4_MeetingAbstracts.914S-a
Abstract PURPOSE: Lung cancer is the most lethal form of cancer for both men and women in the United States. On the basis of histopathological criteria, over 75% of lung cancer cases are classified as non-small cell. In general, patients with non-small cell lung cancer (NSCLC) are poorly responsive or nonresponsive to standard treatments of radio- and chemotherapy, and their prognosis is very poor. Because chemotherapy and irradiation induce programmed cell death or apoptosis in vitro and in vivo, efforts are now being made to define the molecular events underlying or opposing the apoptotic process in NSCLC. Recent findings indicate that multiple human NSCLC cell lines (including A549 lung adenocarcinoma cells) have constitutively active levels of the transcription factor STAT3 that are linked to cell survival. Since STAT1 opposes the actions of STAT3 in many cell types, we tested the hypothesis that STAT1 has antigrowth effects in A549 cells. METHODS: A549 cell were obtained from ATCC and grown in medium supplemented with antibiotics and serum. Before an experiment, cells were serum-starved overnight. Western immunoblotting of whole cell lysates was used to assess STAT1 activation. Cell number was determined with a hemocytometer. RESULTS: Treatment of A549 cells with IFN-γ (10 ng/ml) induced robust STAT1 activation as indicated by increased Tyr701 phosphorylation. Activation was rapid and sustained out to 90 min (62 ± 12-fold increase over control). We next assessed the effect of IFN-γ on cell growth. Treatment of A549 cells for 72 h with IFN-γ (10 ng/ml) resulted in a 75% decrease in cell number. However, prior infection of A549 cells with adenovirus expressing the naturally occurring STAT1 inhibitor PIASy relieved this inhibition. Over 72 h, cell number increased by 150% compared to IFN-γ-treated cells infected with control adenovirus. CONCLUSION: IFN-γ opposes proliferative growth of A549 non-small cell lung cancer cells by activating the STAT1 transcription factor. CLINICAL IMPLICATIONS: Our findings support the idea that STAT1 signaling could be a novel therapeutic target in the treatment of non-small cell lung cancer. DISCLOSURE: N. Salamat, None. Wednesday, October 27, 2004 12:30 PM - 2:00 PM
Activation of STAT1 By IFN-γ Inhibits Growth of Human Non-Small Cell Lung Cancer Cells Nikhat Salamat, MD*; Steve A. Maxwell, PhD; J. R. Brewer, BS; Jonathan N. Day, BS; Richard E. Winn, MD; George W. Booz, PhD Scott and White Hospital, Temple, TX Chest Chest. 2004;126(4_MeetingAbstracts):914S. doi:10.1378/chest.126.4_MeetingAbstracts.914S-a
Abstract PURPOSE: Lung cancer is the most lethal form of cancer for both men and women in the United States. On the basis of histopathological criteria, over 75% of lung cancer cases are classified as non-small cell. In general, patients with non-small cell lung cancer (NSCLC) are poorly responsive or nonresponsive to standard treatments of radio- and chemotherapy, and their prognosis is very poor. Because chemotherapy and irradiation induce programmed cell death or apoptosis in vitro and in vivo, efforts are now being made to define the molecular events underlying or opposing the apoptotic process in NSCLC. Recent findings indicate that multiple human NSCLC cell lines (including A549 lung adenocarcinoma cells) have constitutively active levels of the transcription factor STAT3 that are linked to cell survival. Since STAT1 opposes the actions of STAT3 in many cell types, we tested the hypothesis that STAT1 has antigrowth effects in A549 cells. METHODS: A549 cell were obtained from ATCC and grown in medium supplemented with antibiotics and serum. Before an experiment, cells were serum-starved overnight. Western immunoblotting of whole cell lysates was used to assess STAT1 activation. Cell number was determined with a hemocytometer. RESULTS: Treatment of A549 cells with IFN-γ (10 ng/ml) induced robust STAT1 activation as indicated by increased Tyr701 phosphorylation. Activation was rapid and sustained out to 90 min (62 ± 12-fold increase over control). We next assessed the effect of IFN-γ on cell growth. Treatment of A549 cells for 72 h with IFN-γ (10 ng/ml) resulted in a 75% decrease in cell number. However, prior infection of A549 cells with adenovirus expressing the naturally occurring STAT1 inhibitor PIASy relieved this inhibition. Over 72 h, cell number increased by 150% compared to IFN-γ-treated cells infected with control adenovirus. CONCLUSION: IFN-γ opposes proliferative growth of A549 non-small cell lung cancer cells by activating the STAT1 transcription factor. CLINICAL IMPLICATIONS: Our findings support the idea that STAT1 signaling could be a novel therapeutic target in the treatment of non-small cell lung cancer. DISCLOSURE: N. Salamat, None. Wednesday, October 27, 2004 12:30 PM - 2:00 PM