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- W2198300145 abstract "Colorectal cancer is the third most common cause of death worldwide and despitemany advances in recent years resistance to apoptosis induced by chemotherapeuticdrugs, such as 5-fluorouracil (5-FU), remains a serious issue. A better understandingof how chemotherapeutic drugs induce apoptosis in colon cancer cells will betterinform us on how to develop novel therapeutic strategies to overcome this resistance.We investigated cell death induced by 5-FU in the colon cancer cell line HCT116, andfound that not only cell death, but also cytochrome-c release was dependent on anupstream caspase activity. Upon further investigation, we discovered a large (1-2MDa) apoptosis-inducing complex forming following 5-FU-mediated RNA stress.This complex could be purified and identified by sucrose gradient densityfractionation and was found to contain the core components caspase-8, FADD andRIP1 with interaction from Bid. In the absence of caspase-8 and FADD, complexformation and apoptosis was abolished. This complex forms without involvement ofdeath receptors such as CD95 or the TRAIL receptors DR4 and DR5 despite a clearupregulation of DR5 protein levels following 5-FU. Futhermore, knocking down DR5had no effect on initial caspase-8 cleavage and did not prevent complex formation.This complex forms upstream of the mitochondria, evidenced by overexpression ofBcl-2 or knocking down Bax or Bid. In addition we could demonstrate the inducibleinteraction between the complex members caspase-8 and FADD as well as FADDwith RIP1 by co-immunoprecipitation, and the inducible interaction of FADDmolecules following 5-FU stimulation.We also explored the contribution of the 5-FU-induced DR5 upregulation to Tumournecrosis-factor related apoptosis-inducing ligand (TRAIL)-induced apoptosis inHCT116 cells. TRAIL selectively induces rapid apoptosis in most tumour cell types,and represents a promising anti-cancer agent. Subtoxic doses of TRAIL-inducedapoptosis could be enhanced by co-treatment with low doses of 5-FU in a caspase dependent manner. Sensitisation to TRAIL involved enhanced DR5 expression andactivation of the caspase cascade. Our results demonstrate that caspase-8 expression isnecessary for this 5-FU-mediated TRAIL sensitivity. Finally, we demonstrated thatlow-dose 5-FU pre-treatment sensitises HCT116 cells to Mesenchymal stem cellmediateddelivery of sTRAIL in vitro." @default.
- W2198300145 created "2016-06-24" @default.
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- W2198300145 date "2012-09-28" @default.
- W2198300145 modified "2023-09-27" @default.
- W2198300145 title "The Molecular Mechanisms of 5-Fluorouracil-Induced Apoptosis in Human Colorectal Cancer Cells and the Use of 5-FU as a Sensitising Agent to TRAIL" @default.
- W2198300145 hasPublicationYear "2012" @default.
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