The members of the Bcl-2 family are the central regulators of various cell death modalities. Some of these proteins contribute to apoptosis, while others counteract this type of programmed cell ...death, thus balancing cell demise and survival. A disruption of this balance leads to the development of various diseases, including cancer. Therefore, understanding the mechanisms that underlie the regulation of proteins of the Bcl-2 family is of great importance for biomedical research. Among the members of the Bcl-2 family, antiapoptotic protein Mcl-1 is characterized by a short half-life, which renders this protein highly sensitive to changes in its synthesis or degradation. Hence, the regulation of Mcl-1 is of particular scientific interest, and the study of Mcl-1 modulators could aid in the understanding of the mechanisms of disease development and the ways of their treatment. Here, we summarize the present knowledge regarding the regulation of Mcl-1, from transcription to degradation, focusing on aspects that have not yet been described in detail.
Mitochondria in addition to be a main cellular power station, are involved in the regulation of many physiological processes, such as generation of reactive oxygen species, metabolite production and ...the maintenance of the intracellular Ca
homeostasis. Almost 100 years ago Otto Warburg presented evidence for the role of mitochondria in the development of cancer. During the past 20 years mitochondrial involvement in programmed cell death regulation has been clarified. Moreover, it has been shown that mitochondria may act as a switchboard between various cell death modalities. Recently, accumulated data have pointed to the role of mitochondria in the metastatic dissemination of cancer cells. Here we summarize the modern knowledge concerning the contribution of mitochondria to the invasion and dissemination of tumor cells and the possible mechanisms behind that and attempts to target metastatic cancers involving mitochondria.
BNIP3 in Lung Cancer: To Kill or Rescue? Gorbunova, Anna S.; Yapryntseva, Maria A.; Denisenko, Tatiana V. ...
Cancers,
11/2020, Letnik:
12, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Bcl-2/adenovirus E1B 19kDa interacting protein 3 (BNIP3) is a pro-apoptotic BH3-only protein of the Bcl-2 family. Initially, BNIP3 was described as one of the mediators of hypoxia-induced apoptotic ...cell death in cardiac myocytes and neurons. Besides apoptosis, BNIP3 plays a crucial role in autophagy, metabolic pathways, and metastasis-related processes in different tumor types. Lung cancer is one of the most aggressive types of cancer, which is often diagnosed at an advanced stage. Therefore, there is still urgent demand for reliable biochemical markers for lung cancer and its efficient treatment. Mitochondria functioning and mitochondrial proteins, including BNIP3, have a strong impact on lung cancer development and progression. Here, we summarized current knowledge about the BNIP3 gene and protein features and their role in cancer progression, especially in lung cancer in order to develop new therapeutic approaches associated with BNIP3.
Autophagy is an intracellular self-digestive process involved in catabolic degradation of damaged proteins, and organelles, and the elimination of cellular pathogens. Initially, autophagy was ...considered as a prosurvival mechanism, but the following insights shed light on its prodeath function. Nowadays, autophagy is established as a crucial player in the development of various diseases through interaction with other molecular pathways within a cell. Additionally, disturbance in autophagy is one of the main pathological alterations that lead to resistance of cancer cells to treatment. These autophagy-related pathologies gave rise to the development of new therapeutic drugs. Here, we summarize the current knowledge on the autophagic role in disease pathogenesis, particularly in cancer, and the interplay between autophagy and other cell death modalities in order to combat cancer.
uPAR is a membrane receptor that binds extracellular protease urokinase, contributes to matrix remodeling and plays a crucial role in cellular adhesion, proliferation, survival, and migration. uPAR ...overexpression in tumor cells promotes mitogenesis, opening a prospective avenue for targeted therapy. However, uPAR targeting in cancer has potential risks. We have recently shown that uPAR downregulation in neuroblastoma promotes epithelial-mesenchymal transition (EMT), potentially associated with metastasis and chemoresistance. We used data mining to evaluate the role of uPAR expression in primary and relapsed human neuroblastomas. To model the decreased uPAR expression, we targeted uPAR using CRISPR/Cas9 and shRNA in neuroblastoma Neuro2a cells and evaluated their chemosensitivity in vitro as well as tumor growth and metastasis in vivo. We demonstrate that the initially high
expression predicts poor survival in human neuroblastoma. However, relapsed neuroblastomas have a significantly decreased
expression. uPAR targeting in neuroblastoma Neuro2a cells leads to p38 activation and an increased p21 expression (suggesting a dormant phenotype). The dormancy in neuroblastoma cells can be triggered by the disruption of uPAR-integrin interaction. uPAR-deficient cells are less sensitive to cisplatin and doxorubicin treatment and exhibit lower p53 activation. Finally, low uPAR-expressing Neuro2a cells formed smaller primary tumors, but more frequent metastasis in mice. To the best of our knowledge, this is the first study revealing the pathological role of dormant uPAR-deficient cancer cells having a chemoresistant and motile phenotype.
Lung cancer is the leading cause of cancer mortality worldwide. In recent years, the incidence of lung cancer subtype lung adenocarcinoma (LUAD) has steadily increased. Mitochondria, as a pivotal ...site of cell bioenergetics, metabolism, cell signaling, and cell death, are often dysregulated in lung cancer cells. Mitochondria maintenance and integrity depend on mitochondrial quality control proteins (MQCPs). During lung cancer progression, the levels of MQCPs could change and promote cancer cell adaptation to the microenvironment and stresses. Here, univariate and multivariate proportional Cox regression analyses were applied to develop a signature based on the level of MQCPs (dimeric form of BNIP3, DRP1, and SIRT3) in tumorous and non-tumorous samples of 80 patients with LUAD. The MQCP signature could be used to separate the patients with LUAD into high- and low-risk groups. Survival analysis indicated that patients in the high-risk group had dramatically shorter overall survival compared with the low-risk patients. Moreover, a nomogram combining clinicopathologic features and the MQCP signature was constructed and validated to predict 1-, 3-, and 5-year overall survival of the patients. Thus, this study presents a novel signature based on MQCPs as a reliable prognostic tool to predict overall survival for patients with LUAD.
Caspase-2 is a unique and conservative cysteine protease which plays an important role in several cellular processes including apoptotic cell death. Although the molecular mechanisms of its ...activation remain largely unclear, a major role belongs to the architecture of the caspase-2 active center. We demonstrate that the substitution of the putative phosphorylation site of caspase-2, Serine-384 to Alanine, blocks caspase-2 processing and decreases its enzymatic activity. Strikingly, in silico analysis using molecular dynamics simulations has shown that Serine-384 is crucially involved in interactions within the caspase-2 active center. It stabilizes Arginine-378, which forms a crucial hydrogen bond with the aspartate residue of a substrate. Hence, Serine-384 is essential for supporting a proper architecture of the active center of caspase-2. Moreover, molecular modeling strongly proved steric inaccessibility of Ser-384 to be phosphorylated. Importantly, a multiple alignment has demonstrated that both Serine-384 and Arg-378 residues are highly conservative across all members of caspase family, which allows us to suggest that this diade is indispensable for caspase processing and activity. Spontaneous mutations in this diade might influence oncosuppressive function of caspases, in particular of caspase-2. Likewise, the mutation of Ser-384 is associated with the development of lung squamous cell carcinoma and adenocarcinoma. Taken together, we have uncovered a central feature of the caspase-2 activation mechanism which is crucial for the regulation of its signaling network.
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