SMAC mimetics or forced SMAC expression sensitizes malignancy cells to apoptosis induced by numerous classes of anticancer brokers, including chemotherapeutics, radiation, death receptor agonists and kinase inhibitors, by enhancing caspase activation (64), release of endogenous SMAC (87) and cIAP1/2 degradation (20). 7. facilitated by SMAC/Diablo and HtrA2/Omi, which antagonize the inhibitors of apoptosis (IAP) family of proteins. AIF and Endo G promote DNA degradation (7-8). In cells with low levels of DISC, caspase-8-dependent cleavage of the BH3-only protein Bid generates AMAS truncated Bid (tBid) to amplify apoptotic signaling via Bax/Bak and the mitochondria (Physique 1) (5). 2. Deregulation of apoptosis in malignancy Maintenance of tumor phenotypes is usually highly dependent on apoptosis suppression by certain pro-survival proteins, to evade the fate of cell killing imposed by oncogenic stress during neoplastic transformation. Many key pathways controlling apoptosis and cell survival are therefore generally altered in malignancy (1, 9**). Genetic alterations are generally found in the more proximal AMAS components rather than the core apoptotic machinery or downstream effectors, suggesting a strong selective pressure during carcinogenesis to disable nodal points critical for apoptosis initiation, such as p53. Data from genetically manipulated mice also support apoptosis as an important mechanism for AMAS tumor suppression in the intestinal tract. Alterations in the proximal regulators Transcription factors Apoptosis initiation is usually greatly regulated at the level of gene expression. The best analyzed and highly relevant to malignancy are p53 and NF-B transcription factors. p53 is essential for preventing improper cell proliferation and for maintaining genome integrity following genotoxic stress, and is mutated or inactivated in over half of human cancers (6, 9). Tumor-derived p53 mutants are defective in transcription and apoptosis induction (6, 10). NF-B plays a key role in malignancy and inflammation, and its overexpression or activation is usually linked to chemoresistance (11). Upon activation AMAS by pro-inflammatory cytokines, cytoplasmic NF-B is usually released from inhibitor of B (IB), and translocates into the nucleus to regulate gene expression. Well-known antiapoptotic targets of NF-B include Bcl-2-like proteins, IAPs and c-FLIP (11). Protein kinases Kinases are key regulators of normal cell physiology and play crucial functions in the development and progression of human malignancy. Aberrant activation of receptor tyrosine kinases (RTKs) and non-RTKs ultimately contributes to tumor initiation and maintenance of tumor phenotypes such as cell survival, proliferation, migration, and tumor angiogenesis (1, 9), and confers resistance to malignancy therapy (12**). Aberrant activation of RTKs, such as epidermal growth factor receptor (EGFR, erbB1), hepatocyte growth factor (HGF) receptor MET, platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR), engages intracellular kinase cascades such as Ras/b-Raf/ERK and phophotidylinositol-3-kinase (PI3K)/AKT/mTOR. Activation of these non-RTKs is also caused by gene mutations and amplifications in colon cancer (9). Alterations in the Bcl-2 family of proteins Antiapoptotic Bcl-2 family members are frequently overexpressed in solid tumors, while proapoptotic Bcl-2 family members are downregulated or mutated (5). In rare cases, homozygous deletions or inactivating mutations of are found, particularly in DNA mismatch repair deficient colorectal tumors (13). The activities or levels of proapoptotic proteins are often suppressed by oncogenic kinases. For example, PI3K/AKT or ERK inactivates BAD by phosphorylation (14), and suppresses PUMA induction (15-17). ablation in mice prospects to decreased apoptosis and increased Rabbit polyclonal to PLOD3 tumor burden and invasiveness in the GI tract (18**). Alterations in the extrinsic pathway and other apoptotic components In contrast to the deregulation in the upstream regulators or Bcl-2 family, direct impairments of the extrinsic pathway and downstream apoptotic effectors by genetic alterations are generally rare in human malignancy, while altered expression is usually common (3, 19-20). Overexpression of c-FLIP (4), particularly c-FLIP-L, functions as a survival factor in colon cancer (21). Elevated XIAP (22), cIAP2 (23) or reduced SMAC expression (24), are correlated with disease progression, metastasis or poor survival in colon cancer patients. SMAC levels were inversely correlated with cIAP2 levels and tumor grade, and its ablation accelerates malignancy progression in mice (25). Lost expression or deletion of and overexpression of decoy receptors DcR3 or DcR1 (3), (polymorphisms or deletion have been reported in other cancers, however not in colon cancer. 3. Apoptosis induction in colon cancer treatment and resistance mechanisms Induction of apoptosis is usually a major cytotoxic mechanism of anticancer therapies, including radiation, chemotherapy, and targeted therapies (Physique 1) (3, 5, 12, 26). Targeted therapies are expected AMAS to have improved specificity and reduced toxicity, and ultimately help.