Death associated protein 1 is correlated with the clinical outcome of patients with colorectal cancer and has a role in the regulation of cell death

Abstract

Abstract. Death-associated protein 1 (DAP1) is a member of the DAP family and has been implicated in the regulation of cell growth and death including that of cancer cells. However, the roles of DAP1 in clinical cancer and in the regulation of colorectal cancer cells are largely unknown. The present study investigated the expression profile of DAP1 in human colorectal cancer and the impact of DAP1 on apoptosis and the cellular response to 5-FU. Human colorectal cancer specimens (n=94) and human colorectal cancer cell lines HRT18 and HT115 were used. DAP1 transcript and protein were evaluated using quantitative transcript analysis and immunohistochemistry. DAP1-knockdown cells were generated using anti-DAP1 transgene. The results revealed that human colorectal cancer tissues had lower levels of DAP1 when compared with the normal tissues. The reduced levels were associated with higher Dukes' stage and lymph node metastasis. Patients with low DAP1 expression had a markedly reduced survival. Loss of DAP1 in colorectal cancer cells resulted in a gain in cellular migration and loss of their sensitivity of apoptosis to chemotherapeutic agent, 5-FU. DAP1 was found to be correlated with disease progression and long-term survival of the colorectal patients. DAP1 is also a pivotal regulator of the growth and apoptosis and cellular response to chemotherapy agents. IntroductionDAP1 is one of the members of the death-associated protein (DAP) family, first isolated as a gene involved in IFN-γ-induced apoptosis through a technical knockout strategy (TKO), i.e. random inactivation of genes with antisense cDNA libraries (1). The DAP family is comprised of DAP1, DAP2 (DAP kinase), DAP3, DAP4 and DAP5. DAP2 was found to be involved in apoptosis induced by IFN-γ, TNF-α and Fas (2-3). Serine/threonine kinase catalytic activity and the death domain contribute to the pro-apoptotic function. Based on the loss of DAP2 expression in certain types of cancers, it has been proposed as a candidate tumour-suppressor gene. While the clinical significance of other members of the DAP Family that also exhibit death-promoting functions remain largely unknown, there have been recent reports on the possible association between the DAP family and the clinical outcome of patients with malignant diseases, for example breast cancer (4).Induction of apoptosis is an important mechanism of chemotherapeutic agents in the treatment of cancer. Among the DAP family members, DAP3 was found to be a mitochondrial protein that has a specific amino acid sequence to recognise and anchor to mitochondria. Mitochondria play a key role in apoptosis including release of pro-apoptotic substances such as cytochrome c and AIF, production of reactive oxygen species (ROS) and reduction in ATP synthesis (5-8). All of these findings indicate that DAP may be involved in both the intrinsic and extrinsic apoptosis pathways. In addition, it was reported that DAP2 methylation is associated with a reduced response to chemotherapy and poor prognosis in gastric cancer (9).In the present...

DAP1 high expression increases risk of lymph node metastases in squamous cell carcinoma of the oral cavity

“…In a colorectal cancer study, DAP1 was underexpressed in tumor cells compared with normal adjacent cells (Jia et al, 2014). Autophagy has been associated with tumor suppression, with a strong influence on tumorigenesis.…”

“…Autophagy dysregulation has been associated with breast (Wazir et al, 2014) and colorectal cancer (Jia et al, 2014), suggesting its role as a molecular marker of tumor suppression, survival, and disease prognosis. For these reasons, autophagy and DAP1 have become important targets for new cancer therapies (Jia et al, 2014).…”

“…The DAP family includes DAP1, DAP2 (DAP kinase), DAP3, DAP4, and DAP5, which share pro-apoptotic domains. These proteins are related to cell death mediated by tumor necrosis factor alpha and the Fas ligand (Cohen et al, 1999;Jia et al, 2014;Wazir et al, 2014). DAP1 protein expression is related to cell growth and death regulation, including in tumor cells, through negative regulation of autophagy (Jia et al, 2014).…”

“…These proteins are related to cell death mediated by tumor necrosis factor alpha and the Fas ligand (Cohen et al, 1999;Jia et al, 2014;Wazir et al, 2014). DAP1 protein expression is related to cell growth and death regulation, including in tumor cells, through negative regulation of autophagy (Jia et al, 2014). DAP1 is regulated by the mammalian target of rapamycin (mTOR), being functionally silenced in cells present in nutrientrich environments by the inhibitory phosphorylation of mTOR on amino acid residues Ser3 and Ser51.…”

“…For these reasons, autophagy and DAP1 have become important targets for new cancer therapies (Jia et al, 2014).…”