Fig. 7: Hypothetical model for induction of proliferation blockage by ASK. ASncmtRNAs are produced in mitochondria.

The antisense oligonucleotide Andes-1537 binds to the single-stranded loop region of ASncmtRNA-2, creating a substrate for RNase H, which cleaves the transcript in this region. After processing by Dicer, mitochondrial miRNA hsa-miR-4485, and possibly others, are released. By an unknown mechanism, possibly an indirect effect of hsa-miR-4485 expression, several nuclear-encoded miRNAs are increased, mainly hsa-miR-5096 and hsa-miR-3609. In conjunction, all these miRNAs block translation of key cell cycle progression factors, resulting in a drastic inhibition of proliferation. Triggering of apoptosis is mediated by miRNAs targeting survival factors such as survivin