Silencing of Mcl-1 overcomes resistance of melanoma cells against TRAIL-armed oncolytic adenovirus by enhancement of apoptosis

Abstract

Arming of oncolytic viruses with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown as a viable approach to increase the antitumor efficacy in melanoma. However, melanoma cells may be partially or completely resistant to TRAIL or develop TRAIL resistance, thus counteracting the antitumor efficiency of TRAIL-armed oncolytic viruses. Recently, we found that TRAIL resistance in melanoma cells can be overcome by inhibition of antiapoptotic Bcl-2 protein myeloid cell leukemia 1 (Mcl-1). Here, we investigated whether the cytotoxicity of AdV-TRAIL, an oncolytic adenovirus, which expresses TRAIL after induction by doxycycline (Dox), can be improved in melanoma cells by silencing of Mcl-1. Two melanoma cell lines, the TRAIL-resistant MeWo and the TRAIL-sensitive Mel-HO were investigated. Treatment of both cell lines with AdV-TRAIL resulted in a decrease of cell viability, which was caused by an increase of apoptosis and necrosis. The proapoptotic effects were dependent on induction of TRAIL by Dox and were more pronounced in Mel-HO than in MeWo cells. SiRNA-mediated silencing of Mcl-1 resulted in a further significant decrease of cell viability and a further increase of apoptosis and necrosis in AdV-TRAIL-infected MeWo and Mel-HO cells. However, while in absolute terms, the effects were more pronounced in Mel-HO cells, in relative terms, they were stronger in MeWo cells. These results show that silencing of Mcl-1 represents a suitable approach to increase the cytotoxicity of a TRAIL-armed oncolytic adenovirus in melanoma cells. Key messages • Cytotoxicity of TRAIL-expressing adenovirus can be enhanced by silencing of Mcl-1. • The effect occurs in TRAIL-sensitive and TRAIL-resistant melanoma cells. • Increase of apoptosis is the main mechanism induced by Mcl-1 silencing.

Mechanisms underlying reversed TRAIL sensitivity in acquired bortezomib-resistant non-small cell lung cancer cells

“…Controversially, increased levels of Mcl-1 did not trigger TRAIL resistance in the A549BTZR cells. Trametinib-induced FBW7-dependent Mcl-1 ubiquitination and degradation enhanced apoptosis in colorectal cancer cell lines [ 54 ] , while Tolksdorf et al showed that Mcl-1 silencing may overcome the resistance of melanoma cells against TRAIL-armed oncolytic adenovirus [ 55 ] . However, our study showed that this effect is not very strong in NSCLC cells.…”

In vitro and in silico study on the effect of carvedilol and sorafenib alone and in combination on the growth and inflammatory response of melanoma cells

“…Due to such neutralization, Mcl-1 can balance for the loss of other anti-apoptotic Bcl2 proteins in cancer cells, proposing it as a possible significant regulator of anti-apoptotic regulator in tumor cells ( Senichkin et al, 2020 ). Recent studies have shown that Mcl-1 silencing represents an appropriate approach to increase the cytotoxicity of a TRAIL-armed oncolytic adenovirus in melanoma cells ( Tolksdorf et al, 2021 ). The expression of the MCL1 gene is controlled by many transcription factors (e.g., HIF-1 and STAT3) ( Senichkin et al, 2020 ).…”