Abstract
Apoptosis represents a key anti-cancer therapeutic effector mechanism. During apoptosis, mitochondrial outer membrane permeabilization (MOMP) typically kills cells even in the absence of caspase activity. Caspase activity can also have a variety of unwanted consequences that include DNA damage. We therefore investigated whether MOMP-induced caspase-independent cell death (CICD) might be a better way to kill cancer cells. We find that cells undergoing CICD display potent pro-inflammatory effects relative to apoptosis. Underlying this, MOMP was found to stimulate NF-κB activity through the downregulation of inhibitor of apoptosis proteins. Strikingly, engagement of CICD displays potent anti-tumorigenic effects, often promoting complete tumour regression in a manner dependent on intact immunity. Our data demonstrate that by activating NF-κB, MOMP can exert additional signalling functions besides triggering cell death. Moreover, they support a rationale for engaging caspase-independent cell death in cell-killing anti-cancer therapies.
MeSH terms
-
Aniline Compounds / pharmacology
-
Animals
-
Antineoplastic Agents / pharmacology
-
Apoptosis
-
Caspases / metabolism*
-
Colonic Neoplasms / drug therapy
-
Colonic Neoplasms / enzymology*
-
Colonic Neoplasms / immunology
-
Colonic Neoplasms / pathology
-
Genotype
-
HeLa Cells
-
Humans
-
Inflammation Mediators / metabolism*
-
Inhibitor of Apoptosis Proteins / metabolism
-
Macrophage Activation
-
Mice, Inbred BALB C
-
Mice, Inbred NOD
-
Mice, Knockout
-
Mice, SCID
-
Mitochondria / drug effects
-
Mitochondria / enzymology*
-
Mitochondria / immunology
-
Mitochondria / pathology
-
Mitochondrial Membranes / drug effects
-
Mitochondrial Membranes / enzymology*
-
Mitochondrial Membranes / immunology
-
Mitochondrial Membranes / pathology
-
NF-kappa B / deficiency
-
NF-kappa B / metabolism*
-
NF-kappaB-Inducing Kinase
-
Necrosis
-
Permeability
-
Phenotype
-
Protein Serine-Threonine Kinases / metabolism
-
RNA Interference
-
Receptors, Tumor Necrosis Factor, Type I / genetics
-
Receptors, Tumor Necrosis Factor, Type I / metabolism
-
Signal Transduction
-
Sulfonamides / pharmacology
-
Time Factors
-
Transfection
-
Tumor Necrosis Factor-alpha / metabolism
Substances
-
Aniline Compounds
-
Antineoplastic Agents
-
Inflammation Mediators
-
Inhibitor of Apoptosis Proteins
-
NF-kappa B
-
Receptors, Tumor Necrosis Factor, Type I
-
Sulfonamides
-
Tnfrsf1a protein, mouse
-
Tumor Necrosis Factor-alpha
-
Protein Serine-Threonine Kinases
-
Caspases
-
navitoclax