Long Noncoding Mitochondrial RNAs (LncmtRNAs) as Targets for Cancer Therapy

Abstract

Mitochondria are traditionally been viewed as the cell's powerhouse, generating most of its ATP. However, besides this fundamental metabolic role, mitochondria are implicated in diverse other processes, including apoptosis, inflammation and metastasis. These functions are exerted in part by the growing class of long noncoding mitochondrial RNAs (lncmtRNAs). We found that normal human proliferating cells express a family of noncoding mitochondrial RNAs (ncmtRNAs), comprised of sense (SncmtRNA) and antisense (ASncmtRNA). However, tumor cells express only sense transcripts, suggesting that ASncmtRNA downregulation as a cancer new hallmark. The few ASncmtRNAs copies in tumor cells seem essential to tumor cell viability: knockdown of these transcripts with antisense oligonucleotides (ASO) causes massive apoptotic death of tumor cells, preceded by cell cycle arrest. Preclinical assays show that systemic administration of ASO delayed tumor growth in melanoma and renal cancer models and, caused total remission in subcutaneous renal cancer tumors. The same treatment, however, does not affect normal tissue, suggesting this approach for the development of an efficient and safe therapeutic strategy for several cancer types.

Long non-coding RNAs: From disease code to drug role

“…Mitochondrial energy metabolism and functions related to the induction of apoptosis, inflammation, and metastasis are mediated, to a certain extent, by mtlncRNA. The lncRNAs produced by mtlncRNA mainly include sense mtlncRNA (sense non-coding mitochondrial RNAs, SncmtRNA) and antisense non-coding mitochondrial RNA (ASncmtRNA) 138 . Undoubtedly, the regulatory property of mtlncRNA in diseases and its clinical application are of great value.…”

Mitochondrial DNA: Epigenetics and environment

“…ncRNAs involved in the epigenetic regulation of mitochondrial gene expression can be encoded by both the nuclear and mitochondrial genomes, however, it is not clear whether the mtDNA encoded ncRNAs are derived from mitochondrial genes integrated into the nuclear genome (i.e., NUMTs) or are actually transcribed inside the mitochondria (reviewed in Vendramin et al, 2017). DOI 10.1002/em andCorey, 2017;Sas-Chen et al, 2017;Olavarria et al, 2018;Zhao et al, 2018). DOI 10.1002/em andCorey, 2017;Sas-Chen et al, 2017;Olavarria et al, 2018;Zhao et al, 2018).…”

“…The levels of ncRNAs can be altered manipulating cellular and mitochondrial functions during various types of cancer making them a potential target for cancer therapy (reviewed in Bienertova-Vasku et al, 2013; Matsui Environmental andMolecular Mutagenesis. DOI 10.1002/em andCorey, 2017;Sas-Chen et al, 2017;Olavarria et al, 2018;Zhao et al, 2018).…”

The Implications of ncRNAs in the Development of Human Diseases

“…Nonetheless research on mitochondrial lncRNAs (mtlncRNA) has experience enormous progress. When mitochondrial DNA is transcribed, during transcription processing, it generates large non-coding sequences, including mtlncRNA [ 184 ], and sense (SncmtRNA) along with antisense mtlncRNA (ASncmtRNA) [ 185 ]. ASncmtRNA-1 and ASncmtRNA-2 are down-regulated in various tumor tissues [ 186 ] and it has been proposed that antisense nucleotides (ASOs) targeting the remaining few copies of ASncmtRNA, essential for cell survival, induce cell cycle arrest, and later apoptosis specifically in cancer cells.…”