ArticleBritish journal of cancer2010
Oncogenic KRAS sensitises colorectal tumour cells to chemotherapy by p53-dependent induction of Noxa.
Article in British journal of cancer, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 26 citations in OpenAlex.
- Lack of KRAS, NRAS, BRAF and TP53 mutations improves outcome of elderly metastatic colorectal cancer patients treated with cetuximab, oxaliplatin and UFT.Targeted oncology · 2014Trial
- The Effect of Dynamic, In Vivo-like Oxaliplatin on HCT116 Spheroids in a Cancer-on-Chip Model Is Representative of the Response in Xenografts.Micromachines · 2022Article
- Cytotoxicity of combinations of the pan-KRAS inhibitor BAY-293 against primary non-small lung cancer cells.Translational oncology · 2021Article
- NOXA-dependent contextual synthetic lethality of BCL-XL inhibition and "osmotic reprogramming" in colorectal cancer.Cell death & disease · 2020Article
- MiR-204 enhances mitochondrial apoptosis in doxorubicin-treated prostate cancer cells by targeting SIRT1/p53 pathway.Oncotarget · 2017Article
- Oncogenic KRAS sensitizes premalignant, but not malignant cells, to Noxa-dependent apoptosis through the activation of the MEK/ERK pathway.Oncotarget · 2015Article
- KRAS oncogene repression in colon cancer cell lines by G-quadruplex binding indolo[3,2-c]quinolines.Scientific reports · 2015Article
- MicroRNA signatures in chemotherapy resistant esophageal cancer cell lines.World journal of gastroenterology · 2014Article
- p63 the guardian of human reproduction.Cell cycle (Georgetown, Tex.) · 2012Review
- KRAS assay selection: sensitivity and accuracy in clinical application.Molecular biology reports · 2012Article
- Regulation of homeostasis and oncogenesis in the intestinal epithelium by Ras.Experimental cell research · 2011Review
- Synergistic killing of colorectal cancer cells by oxaliplatin and ABT-737.Cellular oncology (Dordrecht, Netherlands) · 2011Article
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
Abstract
backgroundOxaliplatin and 5-fluorouracil (5-FU) currently form the backbone of conservative treatment in patients with metastatic colorectal cancer. Tumour responses to these agents are highly variable, but the underlying mechanisms are poorly understood. Our previous results have indicated that oncogenic KRAS in colorectal tumour cells sensitises these cells to chemotherapy.
methodsFACS analysis was used to determine cell-cycle distribution and the percentage of apoptotic and mitotic cells. A multiplexed RT-PCR assay was used to identify KRAS-controlled apoptosis regulators after exposure to 5-FU or oxaliplatin. Lentiviral expression of short-hairpin RNAs was used to suppress p53 or Noxa.
resultsOncogenic KRAS sensitised colorectal tumour cells to oxaliplatin and 5-FU in a p53-dependent manner and promoted p53 phosphorylation at Ser37 and Ser392, without affecting p53 stabilisation, p21 induction, or cell-cycle arrest. Chemotherapy-induced expression of the p53 target gene Noxa was selectively enhanced by oncogenic KRAS. Suppression of Noxa did not affect p21 induction or cell-cycle arrest, but reduced KRAS/p53-dependent apoptosis after exposure to chemotherapy in vitro and in tumour xenografts. Noxa suppression did not affect tumour growth per se, but strongly reduced the response of these tumours to chemotherapy.
conclusionOncogenic KRAS determines the cellular response to p53 activation by oxaliplatin or 5-FU, by facilitating apoptosis induction through Noxa.
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