Journal Article

Killing a cancer: what are the alternatives?

Watson, Christine J., Kreuzaler, Peter

2012

نظرة عامة

Key Points A number of alternative cell death programmes, such as necroptosis, lysosomal-mediated programmed cell death (LM-PCD) and autophagy have been established alongside classical apoptosis. These are now known to act both as a backup to apoptosis and also as preferred death pathways in certain cell types. Necroptosis can be triggered by a RIP1- and RIP3-containing complex. This complex can form downstream of death receptors or in the cytosol following stress stimuli. It is tightly regulated by the initiator caspase 8, as well as inhibitors of apoptosis (IAPs) and FLICE-like inhibitory protein (FLIP). Hence, caspase inhibitors, as well as second mitochondria-derived activator of caspases (SMAC) mimetics, are strong sensitizers for necroptosis. LM-PCD, which occurs because of a loss of lysosomal integrity, is frequently seen in cancer cells. This is due to increased metabolism and protein turnover, as well as a reduction of important lysosomal structural proteins. Cancer cells are thus particularly responsive to drugs that target the lysosomes, and drugs ranging from lysosomotropic agents to monoclonal antibodies and microtubule-disrupting agents have all been shown to induce LM-PCD. Autophagy can have both tumour suppressive and tumour-promoting activities. Large-scale autophagy can eventually lead to cell death; however, it is not clear precisely how this type of death is induced. Inhibition and induction of autophagy have both proved to be beneficial under certain circumstances, and the decision as to whether inhibition or activation is preferable is still largely empirical. The alternative pathways of cell death prove to be intricately interconnected with many points of convergence, such as JUN N-terminal kinase (JNK), AMP-activated protein kinase (AMPK) or reactive oxygen species (ROS). Necroptosis has LM-PCD as a frequent downstream occurrence, and an impaired lysosomal compartment affects the ability of autophagosomes to mature. These converging and diverging features are increasingly better understood, leading to a number of targeted approaches aimed at these alternative pathways. Research over the past decade has greatly increased our understanding of non-apoptotic programmed cell death events, such as lysosomal-mediated cell death, necroptosis and cell death with autophagy. This Review discusses converging and diverging features of these pathways with a view to developing new therapeutics for cancer. Evading programmed cell death is one of the hallmarks of cancer. Conversely, inducing cell death by pharmacological means is the basis of almost every non-invasive cancer therapy. Research over the past decade has greatly increased our understanding of non-apoptotic programmed cell death events, such as lysosomal-mediated cell death, necroptosis and cell death with autophagy. It is becoming clear that an intricate effector network connects many of these classical and non-classical death pathways. In this Review, we discuss converging and diverging features of these pathways, as well as attempts to exploit this newly gained knowledge pharmacologically to provide therapeutics for cancer.

• الناشر: Nature Publishing Group UK,Nature Publishing Group
• موضوع: 692/699/67/1059 / 70 / 82 / Apoptosis / Autophagy / Autophagy (Cytology) / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Cell Death / Development and progression / Health aspects / Humans / Lysosomes - metabolism / Necrosis / Neoplasms - metabolism / Neoplasms - pathology / Phagocytosis / Receptor-Interacting Protein Serine-Threonine Kinases - metabolism / review-article / Signal Transduction