engleski

Toward elucidating exoribonuclease-dependent mechanisms for the toxicity of and resistance against the anti-cancer drug 5-Fluorouracil

5-Fluorouracil (5-FU) has been widely used to treat solid tumors. The drug is known to inhibit enzymes involved in DNA replication (TK) and RNA processing/modification (Rrp6/EXOSC10). However, the molecular mechanism of 5-FU's anti-proliferative activity is not fully understood and 5-FU resistance is a serious clinical problem. We hypothesize that (i) long non- coding RNAs regulated by Rrp6/EXOSC10 are important for 5-FU toxicity and that (ii) elevated levels of the enzyme may confer 5-FU resistance in cancer cells. We compared the transcriptomes of a wild type yeast strain treated with 5-FU to an rrp6 deletion mutant and identified transcripts that respond to the drug, the RRP6 deletion or both. Furthermore, we discovered that RRP6 overexpression confers 5-FU resistance during vegetative growth. Our data offer interesting leads for the discovery of novel protein-coding and non-coding RNAs that may be involved in 5-FU toxicity, and they indicate that elevated levels of Rrp6 compromise 5-FU activity. These results are potentially important for improving 5-FU based chemotherapy.

5-FU, Rrp6

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