Targeting antisense mitochondrial noncoding RNAs induces bladder cancer cell death and inhibition of tumor growth through reduction of survival and invasion factors

Abstract

Knockdown of the antisense noncoding mitochondrial RNAs (ASncmtRNAs) induces apoptotic death of several human tumor cell lines, but not normal cells, supporting a selective therapy against different types of cancer. In this work, we evaluated the effects of knockdown of ASncmtRNAs on bladder cancer (BCa). We transfected the BCa cell lines UMUC-3, RT4 and T24 with the specific antisense oligonucleotide Andes-1537S, targeted to the human ASncmtRNAs. Knockdown induced a strong inhibition of cell proliferation and increase in cell death in all three cell lines. As observed in UMUC-3 cells, the treatment triggered apoptosis, evidenced by loss of mitochondrial membrane potential and Annexin V staining, along with activation of procaspase-3 and downregulation of the anti-apoptotic factors survivin and Bcl-xL. Treatment also inhibited cell invasion and spheroid formation together with inhibition of N-cadherin and MMP 11. In vivo treatment of subcutaneous xenograft UMUC-3 tumors in NOD/SCID mice with Andes-1537S induced inhibition of tumor growth as compared to saline control. Similarly, treatment of a high-grade bladder cancer PDX with Andes-1537S resulted in a strong inhibition of tumor growth. Our results suggest that ASncmtRNAs could be potent targets for bladder cancer as adjuvant therapy.

MicroRNAs as Factors in Bidirectional Crosstalk Between Mitochondria and the Nucleus During Cellular Senescence

“…How mitosRNAs are exported from mitochondria and imported into the nucleus is still not known (Gammage et al, 2018), however studies about the expression of sense mitochondrial ncRNAs (SncmtRNAs) and antisense mitochondrial ncRNAs (ASncmtRNAs) between normal and cancer cells, demonstrated a cytoplasmic and nuclear localization of these mitochondrial transcripts, reinforcing the concept that they are exported from mitochondria (Villegas et al, 2007;Landerer et al, 2011;Borgna et al, 2020).…”

Non-coding RNA and reprogrammed mitochondrial metabolism in genitourinary cancer

“…This indicates that ASncmtRNAs can be used as a target for therapy in human renal adenocarcinoma ( Borgna et al, 2017 ). In addition, the transfection of Andes-1537S increased cell death and decreased cell metastasis in the UMUC-3 bladder cancer cell line ( Borgna et al, 2020 ).…”

Mutational landscape of gastric adenocarcinoma in Latin America: A genetic approach for precision medicine

“…The compound Andes-1537 developed in Chile targets the antisense non-coding mitochondrial RNA, inducing apoptosis, decreasing proliferative signaling and inhibiting invasion associated proteins. 77 Andes-1537 is currently in phase I clinical trial tested in patients with advance solid tumors, including gastric cancer. 78 …”