Resumen de Introduction to nobel conference: ‘the cell cycle and cell death in disease’
Major breakthroughs in understanding of the fundamental mechanisms of cell cycle regulation and cell death processes were recognized by three Nobel Prizes in Physiology or Medicine during the last 20 years. Thus, in 2001 Leland H. Hartwell, R. Timothy (Tim) Hunt and Paul M. Nurse were awarded the Nobel Prize for their discoveries of key regulators of the cell cycle; in 2002, Sydney Brenner, H. Robert Horvitz and John E. Sulston received the Nobel Prize for discoveries concerning genetic regulation of organ development and programmed cell death; and in 2016, Yoshinori Ohsumi was awarded the Nobel Prize for his discoveries of mechanisms for autophagy.
Almost a half century ago, Kerr et al. suggested that hyperplasia might sometime result from decreased apoptosis rather than increased mitosis [1]. An analysis of crosstalk between the cell cycle and cell death revealed that when a cell picks up the machinery to proliferate, it also acquires an abort pathway, proposing ‘better dead than wrong’ [2]. It became clear that disturbances within this crosstalk could be associated with pathogenesis of various diseases. Thus, too much cell death is associated with neurological and immune disorders, as well as AIDS. Too little cell death, on the other hand, is associated with development of cancer. The greatly improved understanding of cell cycle progression and cell death at the molecular level has opened possibilities for targeting key proteins in these processes.
Research groups and pharmaceutical companies are now trying to design and use modulators of the cell cycle and cell death programs as therapeutic tools. At the recent 3rd Nobel Conference ‘The Cell Cycle and Cell Death in Disease’, which was held at Nobel Forum, Karolinska Institutet, Stockholm, on 8–11 June 2016, novel findings concerning the mechanisms of cell cycle and cell death regulation were presented, and many speakers showed data on application of this knowledge for treatment of human diseases.
Five comprehensive reviews and one experimental study are published in Journal of Internal Medicine, all based on presentations at this meeting.
In two review articles, various aspects of the relationship between cell death mechanisms and HIV are discussed. Thus, Nardacci et al. present evidence for role of autophagy in HIV infection and pathogenesis [3]. HIV infection represents a system in which a virus via several strategies deactivates the autophagy. In fact, HIV influences autophagy in different ways in both infected and bystander cells, which completely depends on their functional characteristics. It has been shown that HIV requires autophagy for completing the early replication steps, whilst it has developed various strategies to avoid the recognition and degradation of the newly synthesized viral particles. Several genes that regulate autophagy, such as ATG7, GABARAPL2, ATG12 and ATG16L2, are required for productive HIV infection. Although the level of autophagy is increased during infection, both the antiviral and immune features of this process are severely inhibited by HIV, through either direct or indirect mechanisms. Inhibition of autophagy by HIV is essential for prevention of the sequestration of HIV proteins within autophagosomes and their degradation within the lysosomes. Accumulating evidence suggests that stimulation of autophagy might have either a positive or a negative effect on HIV infection. The final output may depend on the severity of autophagy induction, because efficient infection was also observed in cells with a moderate number of autophagosomes, whilst infection over a certain threshold overcomes autophagy flux impairment and inhibits HIV replication. Interestingly, the result of altered autophagy caused by HIV is not restricted to prevention of the degradation of viral particles but also can be directly linked to the capability of the virus to dysregulate the immune system and to promote pathogenesis. This may depend on the autophagy alterations in CD4+T cells, macrophages, dendritic cells or even in the central nervous system during HIV infection. Recently, several drugs were developed to influence the level of autophagy in HIV-infected cells. However, the side effect of the persistent induction of autophagy in vivo remains to be carefully assessed.
Inflammation in the central nervous system (CNS) in HIV-associated neurological disorders is discussed by Marie-Lise Gougeon [4]. The infiltration of HIV into the CNS during infection is well known and leads to development of neurological syndromes such as HIV-associated neurocognitive disorders (HAND), characterized by sustained CNS inflammation. Several endogenous factors, known as danger-associated molecular patterns (DAMPs) or alarmins, are released upon tissue damage and trigger the immune system. One of the members of the IL-1 family, interleukin-33 (IL-33), is a nuclear alarmin that is released upon cell damage and plays an important role in a wide range of inflammatory responses, including regulation of the innate immune response after CNS injury. It was recently shown that neurocognitive changes in HIV infection are associated with dysregulation of the IL-33/ST2 axis in the CNS. Moreover, accumulation of IL-33 encouraged by HIV infection of astrocytes and neuronal cells is followed by different manifestations of HIV neuropathogenesis through the induction of neuronal apoptosis, decreased synaptic functions and neuroinflammation. Additional data are required to fully understand the precise mechanism of immune activation in patients with HIV-associated neurocognitive disorders.
Another example of inflammatory disease, eosinophilic esophagitis (EoE), is discussed by Hans-Uwe Simon and colleagues [5]. Although this disease was recognized as a distinct entity about thirty years ago, the main features of its pathogenesis were only recently described. EoE is defined as a chronic inflammatory condition of the oesophagus characterized clinically by symptoms of oesophageal dysfunction, failure to thrive, regurgitation and vomiting. Histologically, this disease is identified by an intense eosinophilic infiltration. It is also associated with changes in the oesophageal epithelium. Interestingly, a link between expression of caspase-14 and epithelial hyperplasia was observed. Earlier, caspase-14 was identified as nonapoptotic caspase involved in epidermal differentiation. The role of caspase-14 in EoE remains to be identified. A key function of IL-13 was documented in the oesophageal inflammation. Several attempts were undertaken in order to use different anti-IL-13 antibodies to treat EoE, and some appear quite promising. At present, the search for additional specific and sensitive markers for EoE is in the focus of research, which should lead to a better understanding of the molecular pathogenesis of this disease.
As mentioned above, crosstalk between various cell death modalities may occur, and this needs to be taken into account for development of novel therapy. Hay-Koren et al. describe how changes in cIAP2, survivin and BimEL expressions characterize the switch from autophagy to apoptosis in prolonged starvation [6]. All three proteins are known players in apoptosis. The first two proteins have anti-apoptotic functions, although via different mechanisms, and the last one is a pro-apoptotic protein belonging to the BH3-only group of Bcl-2 family proteins. Starvation is a common model for investigation of autophagy. However, prolonged starvation, as a continuing stress condition, is often characterized by a switch from autophagy to apoptosis. The authors have shown that this transition is correlated with decreased levels of two anti-apoptotic IAP family proteins, survivin and cIAP2, and a selective increase in the level of BimEL. This ‘molecular signature’ was common to several cell lines in which this transition had occurred. Molecular mechanisms that regulate these changes are described.
Many years ago, ageing was suggested to represent an example of programmed cell death. Tesauro et al. describe a set of changes from endothelial dysfunction to vascular calcification that are associated with arterial ageing [7]. It has been shown that the aged artery is characterized by autophagy, proliferation and migration of smooth muscle cells (SMC), as well as arterial calcification with a progressive increase of mechanical vessel strictness. Nitric oxide leads to inflammation, which is one of the primary pathological mechanisms of ageing related endothelial dysfunction even in the absence of clinical features. SMC proliferation is controlled by age-related changes in microenvironmental stimuli, such as cytokines and extracellular matrix components. Interestingly, SMCs from newborn rats cannot produce high level of nitric oxide on stimulation with interferon plus lipopolysaccharide or IL-1, whereas SMCs from old rats are characterized by distinctly enhanced iNOS activity. Age-related coronary atherosclerotic calcification was documented long ago, suggesting a role of calcification in plaque instability. The formation of microcalcifications can be mediated by apoptosis and release of apoptotic bodies in these areas, indicating a link between ageing and cell death. It is likely that the molecular changes characterizing arterial ageing could be good targets to prevent or slow down the ageing of the arteries as a major risk factor for cardiovascular disorders.
Since early 1970s, the main focus in cell death research has been apoptosis. However, during last decades, it has become increasingly clear that other cell death modalities, such as autophagy, necroptosis, ferroptosis and others, are equally important for maintaining cellular homeostasis. Indeed, disturbances in all cell death modalities are associated with diseases and there is crosstalk between them in cells. There are accumulated evidences that this crosstalk can potentially be targeted to combat these diseases. Notably, in some cases, suppression or activation of one mode of cell death leads to more efficient activation or inhibition of another one, emphasizing the challenges of therapy development. Our contribution includes a discussion of how the improved understanding of the cell cycle and cell death has stimulated the development of novel therapy against human diseases that are due to disruption of normal cell cycle and/or cell death regulation [8].
Significant progress has been made in the development of more efficient cancer therapy via targeting the cell cycle or cell death machineries. Thus, drugs that specifically inhibit various CDKs are already in clinical use, for example Palbociclib. Compounds that target the Bcl-2 family proteins or p53 are either approved by the FDA, or in clinical trials. Importantly, these compounds represent different classes, from small molecules to antibodies. Combination with standard chemotherapeutic drugs could potentially yield synergistic effects.
Several drugs have been developed for the treatment of neurological diseases and inflammation-associated disorders, such as Gout and Crohn's disease. It is hoped that further progress in forthcoming years will lead to greatly improved therapy of many disorders associated with disturbances in the cell cycle and cell death regulation.
It is clear that detailed analysis of the pathways that regulate the cell cycle and the crosstalk between different modes of cell death has not only increased our knowledge about mechanistic aspects of these processes, but more importantly, has laid a foundation for novel therapeutic strategies which target these fundamental processes. The articles published from the meeting, as examples of work presented at the third Nobel Conference on ‘The Cell Cycle and Cell Death in Disease’, clearly show that identification of various ‘decision points’ that regulate the switch between cell life and death provides a multitude of molecular targets, which offer a range of promising options to be exploited for future therapy of human diseases.
