Significance: Oxidative (reactive oxygen species [ROS]) and nitrosative (reactive nitrogen species [RNS]) stress affects many physiological processes, including survival and death. Although high levels of ROS/RNS mainly causes cell death, low levels of free radicals directly modulate the activities of transcriptional factors, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), p53, and nuclear factor (erythroid-derived) 2-like (Nrf2), and regulate numerous protein kinase cascades that participate in the regulation of the cross talk between autophagy and apoptosis. Recent Advances: Low levels of ROS modify Atg4 and high mobility group box 1 (HMGB1) proteins, activate AMP-activated protein kinase (AMPK) and apoptosis signal-regulating kinase/c-Jun N-terminal kinase (JNK) pathways, or transactivate various proteins that could upregulate autophagy, leading to reductions in apoptosis. Transactivation of antioxidant genes blocks apoptosis and serves as a feedback loop to reduce autophagy. Free radicals could also activate protein kinase B (PKB, or Akt), preventing both autophagy and apoptosis. Stimulation of nitric oxide formation causes S-nitrosylation of several kinases, including JNK1 and IκB kinase β, which blocks autophagy and could promote apoptosis. However, S-nitrosylation of some proapoptotic proteins could block apoptosis. Critical Issues: Endoplasmic reticulum and mitochondria are the main sources of free radicals, which play an essential role in the regulation of apoptosis and autophagy. Oxidation of cardiolipin promotes cytochrome c release and apoptosis that potentially could be inhibited by autophagic clearance of damaged mitochondria. Elimination of damaged mitochondria reduces ROS accumulation, creating a feedback loop that causes inhibition of autophagy. Low levels of RNS could inhibit fission of mitochondria, which would block their degradation by autophagy and spare cells from apoptosis. Future Directions: Understanding of mechanisms that regulate the cross talk between cell fates is essential for discovery of therapeutic tools in the strenuous fight against various disorders, including neurodegeneration and cancer. Antioxid. Redox Signal. 21, 86–102.

Autophagy is a catabolic process involved in the turnover of organelles and macromolecules which, depending on conditions, may lead to cell death or preserve cell survival. We found that some lung cancer cell lines and tumor samples are characterized by increased levels of lipidated LC3. Inhibition of autophagy sensitized non-small cell lung carcinoma (NSCLC) cells to cisplatin-induced apoptosis; however, such response was attenuated in cells treated with etoposide. Inhibition of autophagy stimulated ROS formation and treatment with cisplatin had a synergistic effect on ROS accumulation. Using genetically encoded hydrogen peroxide probes directed to intracellular compartments we found that autophagy inhibition facilitated formation of hydrogen peroxide in the cytosol and mitochondria of cisplatin-treated cells. The enhancement of cell death under conditions of inhibited autophagy was partially dependent on caspases, however, antioxidant NAC or hydroxyl radical scavengers, but not the scavengers of superoxide or a MnSOD mimetic, reduced the release of cytochrome c and abolished the sensitization of the cells to cisplatin-induced apoptosis. Such inhibition of ROS prevented the processing and release of AIF (apoptosis-inducing factor) and HTRA2 from mitochondria. Furthermore, suppression of autophagy in NSCLC cells with active basal autophagy reduced their proliferation without significant effect on the cell-cycle distribution. Inhibition of cell proliferation delayed accumulation of cells in the S phase upon treatment with etoposide that could attenuate the execution stage of etoposide-induced apoptosis. These findings suggest that autophagy suppression leads to inhibition of NSCLC cell proliferation and sensitizes them to cisplatin-induced caspase-dependent and -independent apoptosis by stimulation of ROS formation.

S100A4 is a small calcium-binding protein that is commonly overexpressed in a range of different tumor types, and it is widely accepted that S100A4 has an important role in the process of cancer metastasis. In vitro binding assays has shown that S100A4 interacts with the tumor suppressor protein p53, indicating that S100A4 may have additional roles in tumor development. In the present study, we show that endogenous S100A4 and p53 interact in complex samples, and that the interaction increases after inhibition of MDM2-dependent p53 degradation using Nutlin-3A. Further, using proximity ligation assay, we show that the interaction takes place in the cell nucleus. S100A4 knockdown experiments in two p53 wild-type cell lines, A549 and HeLa, resulted in stabilization of p53 protein, indicating that S100A4 is promoting p53 degradation. Finally, we demonstrate that S100A4 knockdown leads to p53-dependent cell cycle arrest and increased cisplatin-induced apoptosis. Thus, our data add a new layer to the oncogenic properties of S100A4 through its inhibition of p53-dependent processes.

Abstract.  Kaminskyy V, Zhivotovsky B (Karolinska Institutet, Stockholm, Sweden). To kill or be killed: how viruses interact with the cell death machinery (Symposium). J Intern Med 2010; 267: 473–482.A virus (from the Latin virus meaning toxin or poison) is a small infectious agent that can only replicate inside the cells of another organism. Viruses are found wherever there is life and have probably existed since living cells first evolved. Viruses do not have their own metabolism and require a host cell to make new products. The range of structural and biochemical (i.e., cytopathic) effects that viruses have on the host cell is extensive. Most viral infections eventually result in the death of the host cell. The causes of death include cell lysis, alterations to the cell’s surface membrane and various modes of programmed cell death. Some viruses cause no apparent changes to the infected cell. Cells in which the virus is latent and inactive show few signs of infection and often function normally. This causes persistent infection and the virus is often dormant for many months or years. Some viruses can cause cells to proliferate without causing malignancy, whereas others are established causes of cancer. Human organisms use a genetically controlled cell death programme that prevents the spreading of viral infection and kills the virus. Between 19 and 21 November 2009, with sponsorship from the Journal of Internal Medicine, the Swedish Research Foundation and the Swedish Cancer Society hosted a conference in Stockholm entitled: ‘To kill or to be killed. Viral evasion strategies and interference with cell death machinery’. Four comprehensive reviews from this conference are presented in this issue of the Journal of Internal Medicine. These reviews include descriptions of: the modulation of host innate and adaptive immune defenses by cytomegalovirus; the impact of gamma‐chain family cytokines on T cell homoeostasis in HIV‐1 infection and the therapeutic implications; approaches to killing tumours by depriving them of the mechanisms for detoxification; and viral strategies for the evasion of immunogenic cell death.

Longitudinal bone growth takes place in epiphyseal growth plates located in the ends of long bones. The growth plate consists of chondrocytes traversing from the undifferentiated (resting zone) to the terminally differentiated (hypertrophic zone) stage. Autophagy is an intracellular catabolic process of lysosome-dependent recycling of intracellular organelles and protein complexes. Autophagy is activated during nutritionally depleted or hypoxic conditions in order to facilitate cell survival. Chondrocytes in the middle of the growth plate are hypoxic and nutritionally depleted owing to the avascular nature of the growth plate. Accordingly, autophagy may facilitate their survival. To explore the role of autophagy in chondrocyte survival and constitutional bone growth, we generated mice with cartilage-specific ablation of either Atg5 (Atg5cKO) or Atg7 (Atg7cKO) by crossing Atg5 or Atg7 floxed mice with cartilage-specific collagen type 2 promoter–driven Cre. Both Atg5cKO and Atg7cKO mice showed growth retardation associated with enhanced chondrocyte cell death and decreased cell proliferation. Similarly, inhibition of autophagy by Bafilomycin A1 (Baf) or 3-methyladenine (3MA) promoted cell death in cultured slices of human growth plate tissue. To delineate the underlying mechanisms we employed ex vivo cultures of mouse metatarsal bones and RCJ3.IC5.18 rat chondrogenic cell line. Baf or 3MA impaired metatarsal bone growth associated with processing of caspase-3 and massive cell death. Similarly, treatment of RCJ3.IC5.18 chondrogenic cells by Baf also showed massive cell death and caspase-3 cleavage. This was associated with activation of caspase-9 and cytochrome C release. Altogether, our data suggest that autophagy is important for chondrocyte survival, and inhibition of this process leads to stunted growth and caspase-dependent death of chondrocytes. © 2015 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).