Abstract
IFN-γ plays a critical role in tumor immunosurveillance by affecting either immune cells or tumor cells; however, IFN-mediated effects on tumor elimination are largely unknown. In this study, we showed that IFN regulatory factors (IRF) modulated by IFNs up- and downregulated Noxa expression, a prodeath BH3 protein, in various cancer cells. Inhibition of Noxa expression using short hairpin RNA in tumor cells leads to resistance against lipopolysaccharide (LPS)-induced tumor elimination, in which IFN-γ is known as a critical effecter in mice. Chromatin immunoprecipitation analysis in both CT26 cells and SP2/0 cells, sensitive and resistant to LPS-induced tumor elimination, respectively, revealed that the responsiveness of IRF1, 3, 4, and 7 in the Noxa promoter region in response to IFN-γ might be crucial in LPS-induced tumor elimination. IRF1, 3, and 7 were upregulated by IFN-γ and activated Noxa expression, leading to the death of Noxa wild-type baby mouse kidney (BMK) cells but not of Noxa-deficient BMK cells. In contrast, IRF4 acts as a repressor for Noxa expression and inhibits cell death induced by IRF1, 3, or 7. Therefore, although IFN-γ alone are not able to induce cell death in tumor cells in vitro, Noxa induction by IFN-γ, which is regulated by the balance between its activators (IRF1, 3, and 7) and its repressor (IRF4), is crucial to increasing the susceptibility of tumor cells to immune cell-mediated cytotoxicity.
Highlights
The immune system can recognize and eliminate primary transformed tumor cells through a complicated process known as tumor immunosurveillance [1, 2]
We have found that IFN-g alters BH3 profiles by upregulating and downregulating prodeath and antideath BH3 proteins, respectively, and that Noxa induction by IFN-g, which is regulated by the balance between its activators [IFN regulatory factors (IRF)1, 3, and 7] and its repressor (IRF4), is crucial to increasing the susceptibility of tumor cells to immune cell-mediated cytotoxicity
It is worth noting that LPS itself showed little or no death-inducing activity in CT26 or SP2/ 0 cells. These results indicate that tumors bearing CT26 cells can be eliminated by LPS due to LPS-induced increased expression of prodeath BH3 proteins and decreased expression of antideath BH3 proteins; it follows from our previous observations that tumors bearing SP2/0 cells cannot be eliminated by LPS due to the increased expression levels of antideath BH3 proteins and the absence of any induction of the prodeath BH3 proteins Noxa, Bim, and Bad
Summary
The immune system can recognize and eliminate primary transformed tumor cells through a complicated process known as tumor immunosurveillance [1, 2]. Various cytokines, including IFN-g [3,4,5], perforin [6], granulocyte macrophage colony stimulating factor 7), TNF-related apoptosis-inducing ligand [8], and interleukin 12 [9] have been implicated in the process of tumor cell elimination by immune cells. The inhibitory effect of IFN-g on tumor cell growth was first identified when mice transplanted with tumor cells. Authors' Affiliations: 1Department of Biochemistry, Chosun University School of Medicine, Dong-Gu, Gwang-Ju, Republic of Korea; 2Department of Dermatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas; 3Lady Davis Institute, Jewish General Hospital and Departments of Microbiology and Medicine, McGill University, Montreal, Quebec, Canada; and 4Faculty of Pharmacy, Chung-Ang University School of Pharmacy, Seoul, Republic of Korea.
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