Promotion of TRAIL/Apo2L‐induced apoptosis by low‐dose interferon‐β in human malignant melanoma cells

Abstract

Interferon β (IFN‐β) is considered a signaling molecule with important therapeutic potential in cancer since IFN‐β‐induced gene transcription mediates antiproliferation and cell death induction. Whereas, TNF‐related apoptosis inducing ligand/Apo2 ligand (TRAIL/Apo2L) has emerged as a promising anticancer agent because it induces apoptosis specifically in cancer cells. In this study, we elucidated that IFN‐β augments TRAIL‐induced apoptosis synergistically using five human malignant melanoma cells. All of these cells were induced apoptosis by TRAIL. Whereas, the response against IFN‐β was different in amelanotic cells (A375 and CRL1579) and melanotic cells (G361, SK‐MEL‐28, and MeWo). The responsibility of amelanotic cells against IFN‐β was higher than those of melanotic cells. The synergism of IFN‐β and TRAIL were correlated with the responsibilities of the cells against IFN‐β. The synergistic interaction was confirmed by a combination index based on the Chou‐Talalay method. The upregulation of apoptosis in amelanotic cells was caused by very low doses of IFN‐β (over 0.1 IU/ml). Both of p53‐mediated intrinsic pathway and Fas‐related extrinsic pathway were activated by IFN‐β alone and combination with TRAIL. Further, TRAIL death receptors (DR4 and DR5) were upregulated by a low‐dose IFN‐β (over 0.1 IU/ml) and the expression was more promoted by the combination with TRAIL. It was clarified that the upregulation of DR5 is associated with the declination of viability.

Countering TRAIL Resistance in Melanoma

“…With regard to melanoma cells, several distinct strategies were identified that could sensitize TRAIL-induced apoptosis. These included chemotherapeutics, irradiation, endoplasmatic reticulum (ER) stress induction, natural compounds, HDAC (histone deacetylase) inhibitors, metabolic inhibitors and signaling inhibitors, reviewed in [27], as well as inhibition of TAK1 (transforming growth factor β-activated kinase 1) [77] and interferon-β [78]. In addition, survival pathway inhibitors, presently considered for the clinic, resulted in enhanced TRAIL-induced apoptosis and were able to overcome induced TRAIL resistance, including inhibitors for BRAF and MEK [13,79], PI3K/AKT [59], ABL [80], ATM [81], PKC [82], and IKK [83].…”

The deubiquitinase Usp27x as a novel regulator of cFLIPL protein expression and sensitizer to death-receptor-induced apoptosis

“…Type 1 interferon has been reported to enhance apoptosis in melanoma cells [ 44 ] and is dependent on the phosphorylation and dimerization of the transcription factor IRF3. Expression of Usp27x did not alter the phosphorylation-status of TBK1 in WM1158 cells, nor the downstream phosphorylation of IRF3 or the levels of TRIF, TRAF3 and TBK1 proteins (Fig.…”

Double-edged effects of interferons on the regulation of cancer-immunity cycle

“… 99 , 100 Mechanistically, IFN-α and IFN-β induce the transcription of the TP53 gene, inhibit proliferation, and induce apoptosis of cancer cells. 101 Moreover, they also directly induce the production of pro-apoptotic factors, such as TRAIL and FAS 102 , 103 and enhance their pro-apoptotic effects in various malignant cell types. 104 , 105 Additionally, IRF family members are well-known ISGs induced by type I IFNs.…”