Interferon-γ regulates cell malignant growth via the c-Abl/HDAC2 signaling pathway in mammary epithelial cells

Abstract

Interferon-γ (IFN-γ) has been used to control cancers in clinical treatment. However, an increasing number of reports have suggested that in some cases effectiveness declines after a long treatment period, the reason being unclear. We have reported previously that long-term IFN-γ treatment induces malignant transformation of healthy lactating bovine mammary epithelial cells (BMECs) in vitro. In this study, we investigated the mechanisms underlying the malignant proliferation of BMECs under IFN-γ treatment. The primary BMECs used in this study were stimulated by IFN-γ (10 ng/mL) for a long term to promote malignancy. We observed that IFN-γ could promote malignant cell proliferation, increase the expression of cyclin D1/cyclin-dependent kinase 4 (CDK4), decrease the expression of p21, and upregulate the expression of cellular-abelsongene (c-Abl) and histone deacetylase 2 (HDAC2). The HDAC2 inhibitor, valproate (VPA) and the c-Abl inhibitor, imatinib, lowered the expression level of cyclin D1/CDK4, and increased the expression level of p21, leading to an inhibitory effect on IFN-γ-induced malignant cell growth. When c-Abl was downregulated, the HDAC2 level was also decreased by promoted proteasome degradation. These data suggest that IFN-γ promotes the growth of malignant BMECs through the c-Abl/HDAC2 signaling pathway. Our findings suggest that long-term application of IFN-γ may be closely associated with the promotion of cell growth and even the carcinogenesis of breast cancer.

IFN-γ drives inflammatory bowel disease pathogenesis through VE-cadherin–directed vascular barrier disruption

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Carfilzomib inhibits the growth of lung adenocarcinoma via upregulation of Gadd45a expression

“…Proteasome is regarded as a multi-catalytic proteinase complex via eliminating intracellular damaged, misfolded, and short half-life functional proteins. It also plays a critical role in cell cycle control, apoptosis, and response to cell stress (Orlowski and Kuhn, 2008;Ren et al, 2019). Proteasome inhibitors have shown efficient anti-tumor activity both in vitro and in vivo.…”

Ubiquitin‑like modifier‑activating enzyme 7 as a marker for the diagnosis and prognosis of breast cancer

“…IFNs have been used with the intent to cure cancer for several years, including breast cancer (30). IFNs have been reported to exert antitumor effects by regulating the immune system and affecting cell proliferation and apoptosis (31). A limitation of the present study was failure to assess the influence of IFNs on UBA7 expression.…”

“…Furthermore, retinoic acid has been demonstrated to induce UBA7 expression, which in turn induces ISGylation of promyelocytic leukaemia/retinoic acid receptor-α protein and causes degradation in acute promyelocytic leukaemia (29). Previous studies have reported that chemopreventive polyphenols (10,30,31), such as curcumin, epigallocatechin gallate and resveratrol, have the ability to influence UBA7 expression by altering the intracellular reactive oxygen species status, which is regulated via the c-Jun N-terminal kinase/nuclear factor erythroid 2-related factor 2 signaling pathway; however, this association exhibits dose-dependent effects (10). IFNs have been used with the intent to cure cancer for several years, including breast cancer (30).…”