6^th International Conference on Cell and Experimental Biology

Micro(mi)RNAs are short noncoding RNAs that through their seed sequence (pos. 2 – 7/8 of the guide strand) regulate cell function by targeting complementary sequences (seed matches) located mostly in the 3′ untranslated region (3′UTR) of mRNAs. Certain short (s)RNAs when loaded into the RNA induced silencing complex (RISC) are toxic to cancer cells by targeting a network of genes that are critical for cell survival, a process we have termed as death induced by survival gene elimination (DISE). DISE involves simultaneous activation of multiple cell death mechanisms by targeting a large network of genes, that likely differs from cell to cell. These toxic sRNAs carry a G-rich 6mer seed region that targets C-rich seed matches mainly located in the 3’UTR of genes in a miRNA-like manner. G-rich seeds are part of the seed of a number of conserved tumor suppressive miRNAs and the ratio of toxic-to-nontoxic miRNAs predicts treatment outcome in ovarian cancer. We demonstrated that sRNAs delivered using multiple delivery vehicles cause tumor regression in different in vivo mouse and rat tumor models of ovarian, prostate and liver cancer with no side effects. DISE works on any cancer, it is effective on therapy resistant cancer cells, cancer cells cannot become resistant to treatment, there is no evidence of toxicity to treated animals, and one can keep treating and/or switch to different delivery methods without losing efficacy. Because it is an evolutionary conserved cell death mechanism, overactive DISE may lead to human diseases that involve tissue degeneration. Alzheimer’s disease (AD) is characterized by progressive neurodegeneration, but the specific events that cause cell death remain poorly understood. The RISC of most cells is occupied by miRNAs with nontoxic 6mer seeds, which may protect them from DISE by blocking loading of sRNAs that carry toxic G-rich 6mer seeds, including miRNAs, tRNA or rRNA fragments. However, during aging miRNA expression decreases in the brain, and toxic sRNAs may enter the RISC more readily leaving cells primed for DISE. We found evidence that DISE contributes to neuronal loss during AD. We analyzed RISC bound sRNAs (R-sRNAs) of multiple in vitro models and in the brains of in vivo AD mouse models, aged mice, and AD patients. We found that in the mouse models that show neurodegeneration and during aging R-sRNAs shift to more toxic seeds. In contrast, in cells that survived in the post-mortem brains of AD patients and the brains of “SuperAgers”, individuals over age 80 who have superior memory performance, R-sRNAs shift to more nontoxic seeds, supporting a protective function of miRNAs. Our data provides first evidence of a contribution of DISE to the neurotoxicity seen in AD. Our data suggests that toxic 6mer seed containing sRNAs can be developed into a general form of cancer therapy and ways to increase the levels of protective miRNAs in the brain may provide a novel way of treating neurodegenerative diseases such as AD.

PDF (Download Full text)