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

J Mol Med (Berl). 2021 Sep;99(9):1279-1291. doi: 10.1007/s00109-021-02081-3. Epub 2021 May 24.

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.

Keywords: Apoptosis; Mcl-1; Melanoma; Oncolytic adenovirus; TRAIL; siRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics*
  • Adenoviridae / metabolism
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Apoptosis*
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing*
  • Genetic Therapy*
  • Humans
  • Melanoma / genetics
  • Melanoma / metabolism
  • Melanoma / therapy*
  • Melanoma / virology
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics*
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Necrosis
  • Oncolytic Virotherapy*
  • Oncolytic Viruses / genetics*
  • Oncolytic Viruses / metabolism
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / therapy*
  • Skin Neoplasms / virology
  • TNF-Related Apoptosis-Inducing Ligand / genetics*
  • TNF-Related Apoptosis-Inducing Ligand / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human