Overexpression of hRFI inhibits 5-fluorouracil-induced apoptosis in colorectal cancer cells via activation of NF-κB and upregulation of BCL-2 and BCL-XL

Abstract

Resistance to apoptosis is one of the important determinants of resistance to 5-fluorouracil (5-FU) in colorectal cancer cells. Human Ring-Finger homologous to Inhibitor of apoptosis protein type (hRFI) is a newly discovered gene that has been shown to inhibit death receptormediated apoptosis in colorectal cancer cells. However, the molecular mechanism of the inhibition of apoptosis is presently unknown. In order to investigate the molecular function of hRFI in the regulation of 5-FU-induced apoptosis in colorectal cancer cells, HCT116 cells were stably transfected with hRFI or LacZ as a control. hRFI overexpression resulted in cellular resistance to 5-FU through an inhibition of the mitochondrial apoptotic pathway and specific upregulation of Bcl-2 and Bcl-XL. Futhermore, hRFI overexpression resulted in the activation of nuclear factor-jB (NF-jB). Inhibition of NF-jB effectively reversed the resistance to apoptosis as well as the upregulation of Bcl-2 and Bcl-XL in the hRFI transfectant, indicating that the activation of NF-jB is the key mechanism for all these findings. Overexpression of hRFI in SW480 and COLO320 colorectal cancer cells similarly resulted in resistance to 5-FU with the activation of NF-jB and upregulation of Bcl-2 and Bcl-XL. hRFI might be a novel therapeutic target for gene therapy in colorectal cancer.

Identification of GAS1 as an Epirubicin Resistance-related Gene in Human Gastric Cancer Cells with a Partially Randomized Small Interfering RNA Library

“…Inhibition of Bcl-2 expression by siRNA transfection could significantly abolish the inhibition of GAS1 on cell survival, which is also consistent with the known role of Bcl-2 as a primary regulator of apoptosis. The phenomenon that apoptosis inhibition through up-regulating Bcl-2 correlates positively with CDDP and 5-FU resistance in various malignant tumors has been reported previously (62)(63)(64)(65)(66), which is consistent with our results. Although it has been indicated that GAS1 could inhibit apoptosis in some systems (67), many studies were supportive that GAS1 was correlated with cell cycle arrest and could act as a tumor suppressor or an inducer of cell death and apoptosis (61).…”

TWEAK/Fn14 signaling mediates gastric cancer cell resistance to 5-fluorouracil via NF-κB activation

“…We also examined Bcl-xL expression because Bcl-xL is regulated by Fn14 and NF-κB (6) and the expression of Bcl-xL is induced by 5-FU. Bcl-xL is also known to be upregulated in 5-FU-resistant colon cancer cells (22). As predicted, Bcl-xL was upregulated following 5-FU treatment in both cell lines (Fig.…”

“…Evidence indicates that management of the mitochondrial apoptotic pathway may, at least in part, contribute to solving the problem of drug resistance. Bcl-2 and Bcl-xL block the release of cytochrome c followed by caspase-3 activation through stabilization of mitochondrial membrane integrity and subsequent regulation of the mitochondrial apoptotic pathway (18,22). Indeed, Bcl-xL is overexpressed in 5-FU-resistant cells and knock-down of Bcl-xL expression promotes sensitivity to 5-FU in colon cancer (29).…”

miR-181a sensitizes resistant leukaemia HL-60/Ara-C cells to Ara-C by inducing apoptosis

“…Many eVorts are being made to develop anticancer drugs that eYciently inhibit Bcl-2. Previous studies have shown that changes in Bcl-2 family are found in several chemotherapy resistance cell line (Colié et al 2009;Doudican et al 2008;Konishi et al 2006). Studies have shown that during Ara-C-based induction chemotherapy in AML patients, Bcl-2 protein levels increased signiWcantly (AndreeV et al 1999).…”