MnSOD protects colorectal cancer cells from TRAIL-induced apoptosis by inhibition of Smac/DIABLO release

Abstract

The mitochondrial enzyme manganese superoxide dismutase (MnSOD) has been shown to have two faces with regard to its role in tumor development. On the one side, it is well documented that overexpression of MnSOD slows down cancer cell growth, whereas on the other side MnSOD also has a metastasis-promoting activity. We set out to examine the role of MnSOD in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, thought to be a first-line tumor surveillance mechanism and failure to undergo apoptosis might contribute to metastasis formation. We show that overexpression of MnSOD at moderate levels is able to protect cells from TRAIL-induced apoptosis. While caspase-8 activation and Bid cleavage were not affected by MnSOD, we detected a marked decrease in caspase-3 activation pointing to a mitochondrial resistance mechanism. Indeed, we found that MnSOD-overexpressing cells showed reduced cytochrome c and no Smac/DIABLO release into the cytosol. The resulting lack of X-linked inhibitor of apoptosis (XIAP) inhibition by cytosolic Smac/DIABLO most likely caused the TRAIL resistance as RNAi against XIAP-rescued caspase-3 activity and TRAIL sensitivity. Our results show that reactive oxygen species are involved in TRAIL-induced Smac/DIABLO release and in TRAIL-triggered apoptosis. Hence, high levels of MnSOD, which decompose and neutralize these reactive oxygen species, might contribute to metastasis formation by allowing disseminated tumor cells to escape from TRAIL-mediated tumor surveillance. As part of TRAIL regimens, adjuvant treatment with XIAP inhibitors in the form of Smac/DIABLO mimetics or MnSOD inhibitors might be able to break TRAIL resistance of malignant tumor cells.

Viral Inhibitor of Apoptosis vFLIP/K13 Protects Endothelial Cells against Superoxide-Induced Cell Death

“…In contrast, only a few of the vFLIP/K13-upregulated genes (9.8%) belonged to the gene ontology group of apoptosis regulation (Table 1). About half of them are known to possess antiapoptotic functions (e.g., BCL2A1, BIRC3, TNFSF13b, and SOD2 [encoding MnSOD]) (30,45,55,72), whereas others are assigned to proapoptotic activities (e.g., RIPK2, TNFRSF19, and RASSF5) (19,33,50).…”

Targeting of XIAP Combined with Systemic Mesenchymal Stem Cell-Mediated Delivery of sTRAIL Ligand Inhibits Metastatic Growth of Pancreatic Carcinoma Cells

“…Western blots were performed as described previously [34]. The surface expression of TRAIL receptors was measured by incubating cells with PE-conjugated mouse anti-human TRAIL-R1 and mouse anti-human TRAIL-R2 as described previously [35].…”

Prognostic and Predictive Biomarkers in Colorectal Cancer: Implications for the Clinical Surgeon

“…The clinical utility of determining low-penetrance risk factors is in early stages of development but may eventually be used to provide risk assessment for patients without syndromic mutations. High preoperative plasma levels associated with worse prognosis 163 Overexpression of TIMP-1 in tumors associated with decreased 5 y survival on multivariate analysis 164 TIMP-1 expression associated with liver and peritoneal metastases 165 MnSOD SOD2 Superoxide anion scavenger in mitochondria that protects cells from ROS; overexpression may also prevent tumor cells from ROS-induced apoptosis 166 Overexpression associated with decreased survival 167 CD44 antigen CD44 Cell surface glycoprotein involved in cell-cell interactions, adhesion and migration Expression and isoform switching associated with increased risk of metastasis and decreased survival [168][169][170] Thymidylate synthase Aurora-A AURKA Serine/threonine kinase associated with centrosome formation and therefore spindle assembly and stability…”