Smac mimetic triggers necroptosis in pancreatic carcinoma cells when caspase activation is blocked.

Publisher: Elsevier Science Ireland Country of Publication: Ireland NLM ID: 7600053 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-7980 (Electronic) Linking ISSN: 03043835 NLM ISO Abbreviation: Cancer Lett Subsets: MEDLINE

Publication: Limerick : Elsevier Science Ireland
Original Publication: Amsterdam, Elsevier/North-Holland.

Amino Acid Chloromethyl Ketones/*pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Caspase Inhibitors/*pharmacology ; Caspases/*metabolism ; Intracellular Signaling Peptides and Proteins/*pharmacology ; Mitochondrial Proteins/*pharmacology ; Oligopeptides/*pharmacology ; Pancreatic Neoplasms/*drug therapy; Apoptosis Regulatory Proteins ; Autocrine Communication/drug effects ; Biological Mimicry ; Dose-Response Relationship, Drug ; Enzyme Activation ; Humans ; Inhibitor of Apoptosis Proteins/antagonists & inhibitors ; Inhibitor of Apoptosis Proteins/metabolism ; Jurkat Cells ; MAP Kinase Kinase Kinases/genetics ; MAP Kinase Kinase Kinases/metabolism ; Necrosis ; Nuclear Pore Complex Proteins/genetics ; Nuclear Pore Complex Proteins/metabolism ; Pancreatic Neoplasms/enzymology ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/pathology ; Paracrine Communication/drug effects ; RNA Interference ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; Receptors, Tumor Necrosis Factor, Type I/genetics ; Receptors, Tumor Necrosis Factor, Type I/metabolism ; Signal Transduction/drug effects ; Time Factors ; Transfection ; Tumor Necrosis Factor-alpha/metabolism

Evasion of apoptosis represents a key mechanism of treatment resistance of pancreatic cancer (PC) and contributes to the poor prognosis of this cancer type. Here, we report that induction of necroptosis is an alternative strategy to trigger programmed cell death in apoptosis-resistant PC cells. We show that the second mitochondrial activator of caspases (Smac) mimetic BV6 that antagonizes inhibitor of apoptosis (IAP) proteins induces necroptosis in PC cells in which apoptosis is blocked by the caspase inhibitor zVAD.fmk. Intriguingly, BV6 switches autocrine/paracrine production of tumor necrosis factor (TNF)α by PC cells into a death signal and also acts in concert with exogenously supplied TNFα to trigger necroptosis, when caspase activation is simultaneously blocked. BV6 stimulates TNFα production and formation of the receptor-interacting protein (RIP)1/RIP3-containing necrosome complex in PC cells. Knockdown of TNF receptor 1 (TNFR1) protects PC cells from BV6- or BV6/TNFα-mediated cell death, demonstrating that TNFα autocrine/paracrine signaling by PC cells contributes to BV6-induced necroptosis. Importantly, genetic silencing of receptor interacting protein kinase 3 (RIPK3) or mixed lineage kinase domain-like protein (MLKL) significantly rescues PC cells from BV6- or BV6/TNFα-induced cell death. Similarly, pharmacological inhibition of RIP1, RIP3 or MLKL significantly reduces BV6- or BV6/TNFα-stimulated cell death. By demonstrating that Smac mimetics can bypass resistance to apoptosis by triggering necroptosis as an alternative form of programmed cell death, our findings have important implications for the design of new treatment concepts for PC.
(Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Keywords: Cell death; IAP proteins; Necroptosis; Pancreatic carcinoma; Smac mimetic

0 (AGFG1 protein, human)
0 (Amino Acid Chloromethyl Ketones)
0 (Antineoplastic Agents)
0 (Apoptosis Regulatory Proteins)
0 (BV6 peptide)
0 (Caspase Inhibitors)
0 (DIABLO protein, human)
0 (Inhibitor of Apoptosis Proteins)
0 (Intracellular Signaling Peptides and Proteins)
0 (Mitochondrial Proteins)
0 (Nuclear Pore Complex Proteins)
0 (Oligopeptides)
0 (RNA-Binding Proteins)
0 (Receptors, Tumor Necrosis Factor, Type I)
0 (TNFRSF1A protein, human)
0 (Tumor Necrosis Factor-alpha)
0 (benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone)
EC 2.7.11.1 (RIPK3 protein, human)
EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinases)
EC 2.7.11.25 (MAP Kinase Kinase Kinases)
EC 2.7.11.25 (MAP3K9 protein, human)
EC 3.4.22.- (Caspases)

Date Created: 20160609 Date Completed: 20170726 Latest Revision: 20191210

20250114

10.1016/j.canlet.2016.05.036

27267809