Background: Down-regulation of the antisense mitochondrial ncRNAs (ASncmtRNAs) is a general vulnerability of cancer cells.Results: Knocking down the ASncmtRNAs induces apoptosis, down-regulation of survivin, and generation of microRNAs.Conclusion: Induction of apoptosis in cancer cells is potentiated by down-regulation of survivin.Significance: The ASncmtRNAs represent a new potential therapeutic target for cancer.
We reported that knockdown of the antisense noncoding mitochondrial RNAs (ASncmtRNAs) induces apoptotic death of several human tumor cell lines, but not normal cells, suggesting this approach for selective therapy against different types of cancer. In order to translate these results to a preclinical scenario, we characterized the murine noncoding mitochondrial RNAs (ncmtRNAs) and performed in vivo knockdown in syngeneic murine melanoma models. Mouse ncmtRNAs display structures similar to the human counterparts, including long double-stranded regions arising from the presence of inverted repeats. Knockdown of ASncmtRNAs with specific antisense oligonucleotides (ASO) reduces murine melanoma B16F10 cell proliferation and induces apoptosis in vitro through downregulation of pro-survival and metastasis markers, particularly survivin. For in vivo studies, subcutaneous B16F10 melanoma tumors in C57BL/6 mice were treated systemically with specific and control antisense oligonucleotides (ASO). For metastasis studies, tumors were resected, followed by systemic administration of ASOs and the presence of metastatic nodules in lungs and liver was assessed. Treatment with specific ASO inhibited tumor growth and metastasis after primary tumor resection. In a metastasis-only assay, mice inoculated intravenously with cells and treated with the same ASO displayed reduced number and size of melanoma nodules in the lungs, compared to controls. Our results suggest that ASncmtRNAs could be potent targets for melanoma therapy. To our knowledge, the ASncmtRNAs are the first potential non-nuclear targets for melanoma therapy.
Background: Antisense mitochondrial ncRNAs are down-regulated during oncogenesis by unknown mechanisms.Results: High risk HPV E2 oncogene induces down-regulation of the antisense transcripts. Additionally, E6 and E7 induce expression of a new sense mitochondrial ncRNA.Conclusion: HPV oncogenes modulate expression of mitochondrial ncRNAs.Significance: During non-viral oncogenesis, cellular factor(s), analogously to E2, could induce down-regulation of the antisense mitochondrial ncRNAs.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations鈥揷itations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.