Egr-1 has been implicated in the control of cell growth, survival and transformation (Thiel and Cibelli, 2002; Ahmed, 2004). Egr-1 has Tofacitinib Citrate order also been connected to the development of human cancers. It has been proposed to have a role in multistage carcinogenesis in the skin (Riggs et al, 2000). High levels of constitutive Egr-1 expression have been observed in most human prostate cancers and found to correlate with more advanced stages of malignancy and poor prognosis (Eid et al, 1998). Moreover, tumour progression in transgenic mouse models of prostate cancer was reported to be significantly impaired when Egr-1 was not expressed (Abdulkadir et al, 2001). Egr-1 basal expression was also found to be much higher in gastric cancer tissues than in normal gastric mucosa and high Egr-1 mRNA expression correlated with metastasis to lymph nodes and remote organs (Kobayashi et al, 2002).

To date, the studies analysing the functions of Egr-1 have been contradictory, with reports of both cytoprotective and pro-apoptotic functions in tumour cells (Huang et al, 1998a; Virolle et al, 2001). Egr-1 induction has been implicated as a key event in response to ionising radiation-induced growth arrest or cell death mediated by Egr-1 target genes such as TNF-��, p53, Retinoblastoma and Bax (Ahmed, 2004). The role of Egr-1 in TRAIL-induced apoptosis is limited. One study showed that Egr-1 negatively regulates survivin expression and hence sensitises cell lines to TRAIL-induced apoptosis (Wagner et al, 2008).

Another study linked Egr-1 to TRAIL that showed that TNF and TRAIL are released from irradiated (IR) tumour cells and induce bystander death of neighbouring/IR-unaffected cells. Although TNF secretion was mediated by Egr-1, TRAIL secretion only occurred in a tumour cells line that did not express functional Egr-1 (Shareef et al, 2007). This study also indicates that during irradiation or genotoxic drug exposure, Egr-1 enhances tumour regression by inducing a bystander effect. Our study found that Egr-1 is not only rapidly induced by TRAIL, but is also constitutively expressed at a relatively high level in many colon carcinoma cell lines. Another study also found Egr-1 upregulation at the mRNA level in early-onset colorectal cancers (Hong et al, 2007). Inhibition of Egr-1 by overexpressing DN-Egr-1 augmented cell death induced by TRAIL through the DR5, but not through the DR4 receptor. The Dacomitinib differential role of DR4 and DR5 may relate to our finding that in HCT15 cells DR4-mediated apoptosis requires mitochondrial amplification whereas DR5 stimulation induces a type I, mitochondrial-independent apoptotic pathway. Inhibition of Egr-1 however did not alter expression of the Bcl-2 family members, Bax, Bcl-2, Bcl-XL or Mcl-1.