Alteration of ribosome function upon 5-fluorouracil treatment favours cancer cell drug-tolerance
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ABSTRACT:
PROVIDER: PRJNA741225 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14904639_1.fastq.gz | Fastqsanger.gz | |||
| SRR14904639_2.fastq.gz | Fastqsanger.gz | |||
| SRR14904641_1.fastq.gz | Fastqsanger.gz | |||
| SRR14904641_2.fastq.gz | Fastqsanger.gz | |||
| SRR14904643_1.fastq.gz | Fastqsanger.gz |
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Project description:Partial response to chemotherapy leads to disease resurgence. Upon treatment, a subpopulation of cancer cells, called drug-tolerant persistent cells, displays a transitory drug tolerance that lead to treatment resistance. Though drug-tolerance mechanisms remain poorly known, they have been linked to non-genomic processes, including epigenetics, stemness and dormancy. 5-fluorouracil (5-FU), the most widely used chemotherapy in cancer treatment, is associated with resistance. While prescribed as an inhibitor of DNA replication, 5-FU alters all RNA pathways. Here, we show that 5-FU treatment leads to the unexpected production of fluorinated ribosomes, exhibiting altered mRNA translation. 5-FU is incorporated into ribosomal RNAs of mature ribosomes in cancer cell lines, colorectal xenografts, and human tumors. Fluorinated ribosomes appear to be functional, yet, they display a selective translational activity towards mRNAs according to the nature of their 5'-untranslated region. As a result, we found that sustained translation of IGF-1R mRNA, which codes for one of the most potent cell survival effectors, promoted the survival of 5-FU-treated colorectal cancer cells. Altogether, our results demonstrate that "man-made" fluorinated ribosomes favour the drug-tolerant cellular phenotype by promoting translation of survival genes. This could be exploited for developing novel combined therapies. By unraveling translation regulation as a novel gene expression mechanism helping cells to survive a drug-challenge, our study extends the spectrum of molecular mechanisms driving drug-tolerance.
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Project description:Mechanisms of drug-tolerance remain poorly understood and have been linked to genomic but also to non-genomic processes. 5-fluorouracil (5-FU), the most widely used chemotherapy in oncology is associated with resistance. While prescribed as an inhibitor of DNA replication, 5-FU alters all RNA pathways. Here, we show that 5-FU treatment leads to the production of fluorinated ribosomes exhibiting altered translational activities. 5-FU is incorporated into ribosomal RNAs of mature ribosomes in cancer cell lines, colorectal xenografts, and human tumors. Fluorinated ribosomes appear to be functional, yet, they display a selective translational activity towards mRNAs depending on the nature of their 5'-untranslated region. As a result, we find that sustained translation of IGF-1R mRNA, which encodes one of the most potent cell survival effectors, promotes the survival of 5-FU-treated colorectal cancer cells. Altogether, our results demonstrate that "man-made" fluorinated ribosomes favor the drug-tolerant cellular phenotype by promoting translation of survival genes.
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Project description:Genome-wide alteration of histone3 lysine23 succinylation contribute to 5-fluorouracil resistance in colon cancer cells
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Project description:The control of the protozoan parasite Leishmania relies on few drugs with unknown cellular targets and unclear mode of action. Several antileishmanials, however, were shown to induce apoptosis in Leishmania and this death mechanism was further studied in drug-sensitive and drug-resistant Leishmania infantum. In sensitive parasites, antimonials (SbIII), miltefosine (MF) and amphotericin B (AMB), but not paromomycin (PARO), triggered apoptotic cell death associated with reactive oxygen species (ROS). In contrast, Leishmania mutants resistant to SbIII, MF or AMB not only failed to undergo apoptosis following exposure to their respective drugs, but also were more tolerant towards apoptosis induced by other antileishmanials, provided that these killed Leishmania via ROS production. Such tolerance favored the rapid acquisition of multidrug resistance. PARO killed Leishmania in a non-apoptotic manner and failed to produce ROS. PARO resistance neither protected against drug-induced apoptosis nor provided an increased rate of acquisition of resistance to other antileishmanials. However, the PARO-resistant mutant, but not SbIII-, MF- or AMB-resistant mutants, became rapidly cross-resistant to methotrexate, a model drug also not producing ROS. Our results therefore link the mode of killing of drugs to tolerance to cell death and to a facilitated emergence of multidrug resistance. These findings may have fundamental implications in the field of chemotherapeutic interventions.
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Project description:We use high-density tiling DNA microarray technology to obtain the specific transcriptome-wide response induced by 5-Fluorouracil (5FU) in the eukaryotic model Schizosaccharomyces pombe.
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2012-12-31 | E-GEOD-38591 | biostudies-arrayexpress
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2021-04-29 | E-MTAB-10354 | biostudies-arrayexpress
Project description:This study addressed involvement of fourteen 5-fluorouracil pathway genes in the prognosis of colorectal carcinoma patients. The major goal of our study was to investigate associations of gene expression of enzymes metabolizing 5-fluorouracil with therapy response and survival of colorectal carcinoma patients Downregulation of DPYD and upregulation of PPAT, UMPS, RRM2, and SLC29A1 transcripts were found in tumors compared to adjacent mucosas in testing and validation sets of patients. Low RRM2 transcript level significantly associated with poor response to the first-line palliative 5-FU-based chemotherapy in the testing set and with poor disease-free interval of patients in the validation set.
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Project description:We use high-density tiling DNA microarray technology to obtain the specific transcriptome-wide response induced by 5-Fluorouracil (5FU) in the eukaryotic model Schizosaccharomyces pombe. Schizosaccharomyces pombe cultures with 5FU added to a final concentration of 500 M-NM-<M. Incubation was allowed to proceed for 0, 15, 60 and 240 minutes.Two biological replicates each.
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