IFN-γ Inhibits Growth of WISH Cells in a Cell Cycle Phase-Specific Manner

Abstract

Treatment of WISH (human amnion) cells with interferon-gamma (IFN-gamma) inhibits their growth. Release of the cells from IFN-gamma-mediated growth inhibition led to a rapid and significant increase in DNA synthesis, followed by doubling of cell numbers. The DNA synthesis profile was strikingly similar to that shown by WISH cells released from growth arrest by the G1/S phase inhibitor, aphidicolin. This strongly suggested that IFN-gamma treatment leads to growth inhibition of WISH cells at the G1/S boundary of the cell cycle. In contrast, IFN-alpha blocked growth of these cells at the G0/G1 boundary.

Exposure to Interferon γ Decreases Levels and Activity of Key Cell Cycle Proteins Resulting in Severe Growth Arrest of the Human Non-Transformed Cell Line, WISH

“…The low levels of cyclin E and CDK2 would have resulted in the low levels of cyclin E-CDK2 complex and thereby low levels of active cyclin E-CDK2 complex, leading to arrest of cell cycle progression. Since the active cyclin E-CDK2 complex is required for progression of cell cycle through G1/S boundary, these observations are in concurrence with our earlier findings that IFNg detains WISH cells at G1/S boundary by effecting growth-arrest in late G1 phase (Supriya et al, 1998;Vashistha et al, 2007). The molecular mechanisms that lead to the down regulation of the levels of cyclin E require further detailed investigations.…”

“…Proliferation of WISH cells was inhibited within the first 12 hrs of exposure to IFNg (Figure 1A), with accumulation of the cells in G1 phase of cell cycle (Figure 1B), as reported earlier by us (Supriya et al, 1998;Vashistha et al, 2007). Induction of STAT1α, upto a level JCST/Vol.3 Issue 1 of 1.5-fold of the levels in the untreated cells, could be observed in WISH cells as early as 30 min post-treatment (Figure 2A), with the levels peaking to 5.6-fold at 24 hrs post-treatment.…”

“…For this purpose, the non-transformed human cell line, WISH, was chosen. In this regard, we had earlier reported that WISH cells, which are growth-arrested by IFNg, are detained at a point prior to DNA synthesis in a reversible manner and that the IFN acts within the first 11 hrs in G1 phase of the cell cycle (Supriya et al, 1998;Vashistha et al, 2007). These observations prompted us to examine the levels and/or activity of G1-and G1/S-specific cell cycle proteins.…”

Involvement of Proteases in the Action of IFN-γon WISH Cells

“…(25,26) Other studies have presented evidence of cell growth arrest and inhibition of DNA synthesis without the induction of apoptosis following exposure of various cell lines to IFN-g. (27,28) It has also been shown that the antiproliferative effect of IFN-g on WISH cells, as well as on other cells, is achieved by arresting the cells at the G 1 /S or G 2 /M boundary phase of the cell cycle. (29)(30)(31) Hence, we suggest that TLP may be involved in processes leading to these activities.…”

Inhibition of the EGF receptor and ERK1/2 signaling pathways rescues the human epidermoid carcinoma A431 cells from IFNγ-induced apoptosis

“…1,22 IFNγ also is able reversibly to block the cell growth at G 1 /S boundary of cell cycle. 23,24 STAT1 has been implicated in apoptosis in response to IFNγ stimulation. STAT1 positively regulates the expression of gene encoding many antiproliferative and proapoptotic molecules such as IFNγ regulatory factor 1 (IRF-1), 2,[25][26][27] …”