scholarly journals Autophagy Paradox of Cancer: Role, Regulation, and Duality

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Amit Kumar Verma ◽  
Prahalad Singh Bharti ◽  
Sahar Rafat ◽  
Deepti Bhatt ◽  
Yamini Goyal ◽  
...  
Keyword(s):  
Growth Factors ◽  
Energy Level ◽  
Cellular Materials ◽  
Cancer Therapies ◽  
Tumor Suppressor Proteins ◽  
Hypoxic Conditions ◽  
Pathological Conditions ◽  
Evolutionarily Conserved ◽  
Advanced Stages ◽  
Catabolic Process

Autophagy, a catabolic process, degrades damaged and defective cellular materials through lysosomes, thus working as a recycling mechanism of the cell. It is an evolutionarily conserved and highly regulated process that plays an important role in maintaining cellular homeostasis. Autophagy is constitutively active at the basal level; however, it gets enhanced to meet cellular needs in various stress conditions. The process involves various autophagy-related genes that ultimately lead to the degradation of targeted cytosolic substrates. Many factors modulate both upstream and downstream autophagy pathways like nutritional status, energy level, growth factors, hypoxic conditions, and localization of p53. Any problem in executing autophagy can lead to various pathological conditions including neurodegeneration, aging, and cancer. In cancer, autophagy plays a contradictory role; it inhibits the formation of tumors, whereas, during advanced stages, autophagy promotes tumor progression. Besides, autophagy protects the tumor from various therapies by providing recycled nutrition and energy to the tumor cells. Autophagy is stimulated by tumor suppressor proteins, whereas it gets inhibited by oncogenes. Due to its dynamic and dual role in the pathogenesis of cancer, autophagy provides promising opportunities in developing novel and effective cancer therapies along with managing chemoresistant cancers. In this article, we summarize different strategies that can modulate autophagy in cancer to overcome the major obstacle, i.e., resistance developed in cancer to anticancer therapies.

scholarly journals The Challenging Riddle about the Janus-Type Role of Hsp60 and Related Extracellular Vesicles and miRNAs in Carcinogenesis and the Promises of Its Solution

2021 ◽  
Vol 11 (3) ◽  
pp. 1175
Author(s):  
Sabrina David ◽  
Alessandra Maria Vitale ◽  
Alberto Fucarino ◽  
Federica Scalia ◽  
Giuseppe Vergilio ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Extracellular Vesicles ◽  
Cancer Development ◽  
Cancer Therapies ◽  
Ongoing Research ◽  
Pathological Conditions ◽  
Anti Cancer ◽  
Evolutionarily Conserved ◽  
The Impact

Hsp60 is one of the most ancient and evolutionarily conserved members of the chaperoning system. It typically resides within mitochondria, in which it contributes to maintaining the organelle’s proteome integrity and homeostasis. In the last few years, it has been shown that Hsp60 also occurs in other locations, intracellularly and extracellularly, including cytosol, plasma-cell membrane, and extracellular vesicles (EVs). Consequently, non-canonical functions and interacting partners of Hsp60 have been identified and it has been realized that it is a hub molecule in diverse networks and pathways and that it is implicated, directly or indirectly, in the development of various pathological conditions, the Hsp60 chaperonopathies. In this review, we will focus on the multi-faceted role of this chaperonin in human cancers, showing the contribution of intra- and extracellular Hsp60 in cancer development and progression, as well as the impact of miRNA-mediated regulation of Hsp60 in carcinogenesis. There are still various aspects of this intricate biological scenario that are poorly understood but ongoing research is steadily providing new insights and we will direct attention to them. For instance, we will highlight the possible applications of the Hsp60 involvement in carcinogenesis not only in diagnosis, but also in the development of specific anti-cancer therapies centered on the use of the chaperonin as therapeutic target or agent and depending on its role, pro- or anti-tumor.

scholarly journals Tumor Suppression and Promotion by Autophagy

2014 ◽  
Vol 2014 ◽  
pp. 1-15 ◽  
Author(s):  
Yenniffer Ávalos ◽  
Jimena Canales ◽  
Roberto Bravo-Sagua ◽  
Alfredo Criollo ◽  
Sergio Lavandero ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Metabolic Stress ◽  
Lysosomal Degradation ◽  
Tumor Suppressor Proteins ◽  
Pathological Conditions ◽  
Suppressor Mechanism ◽  
Resistance To Chemotherapy ◽  
Catabolic Process

Autophagy is a highly regulated catabolic process that involves lysosomal degradation of proteins and organelles, mostly mitochondria, for the maintenance of cellular homeostasis and reduction of metabolic stress. Problems in the execution of this process are linked to different pathological conditions, such as neurodegeneration, aging, and cancer. Many of the proteins that regulate autophagy are either oncogenes or tumor suppressor proteins. Specifically, tumor suppressor genes that negatively regulate mTOR, such as PTEN, AMPK, LKB1, and TSC1/2 stimulate autophagy while, conversely, oncogenes that activate mTOR, such as class I PI3K, Ras, Rheb, and AKT, inhibit autophagy, suggesting that autophagy is a tumor suppressor mechanism. Consistent with this hypothesis, the inhibition of autophagy promotes oxidative stress, genomic instability, and tumorigenesis. Nevertheless, autophagy also functions as a cytoprotective mechanism under stress conditions, including hypoxia and nutrient starvation, that promotes tumor growth and resistance to chemotherapy in established tumors. Here, in this brief review, we will focus the discussion on this ambiguous role of autophagy in the development and progression of cancer.

scholarly journals Long Term Pharmacological Perturbation of Autophagy in Mice: Are HCQ Injections a Relevant Choice?

Biomedicines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 47 ◽  
Author(s):  
Jean-Daniel Masson ◽  
Benoit Blanchet ◽  
Baptiste Periou ◽  
François-Jérôme Authier ◽  
Baharia Mograbi ◽  
...  
Keyword(s):  
Mouse Models ◽  
In Vivo Studies ◽  
Loss Of Function ◽  
Evolutionarily Conserved ◽  
Atg Genes ◽  
Conditional Inhibition ◽  
The Impact ◽  
Catabolic Process

Macroautophagy (hereafter referred to as autophagy) is an evolutionarily conserved catabolic process whose loss-of-function has been linked to a growing list of pathologies. Knockout mouse models of key autophagy genes have been instrumental in the demonstration of the critical functions of autophagy, but they display early lethality, neurotoxicity and unwanted autophagy-independent phenotypes, limiting their applications for in vivo studies. To avoid problems encountered with autophagy-null transgenic mice, we investigated the possibility of disturbing autophagy pharmacologically in the long term. Hydroxychloroquine (HCQ) ip injections were done in juvenile and adult C57bl/6j mice, at range doses adapted from the human malaria prophylactic treatment. The impact on autophagy was assessed by western-blotting, and juvenile neurodevelopment and adult behaviours were evaluated for four months. Quite surprisingly, our results showed that HCQ treatment in conditions used in this study neither impacted autophagy in the long term in several tissues and organs nor altered neurodevelopment, adult behaviour and motor capabilities. Therefore, we recommend for future long-term in vivo studies of autophagy, to use genetic mouse models allowing conditional inhibition of selected Atg genes in appropriate lineage cells instead of HCQ treatment, until it could be successfully revisited using higher HCQ doses and/or frequencies with acceptable toxicity.

Autophagy Defects in Skeletal Myopathies

2020 ◽  
Vol 15 (1) ◽  
pp. 261-285 ◽  
Author(s):  
Marta Margeta
Keyword(s):  
Clinical Presentation ◽  
Critical Role ◽  
Lysosomal Degradation ◽  
Cellular Mechanisms ◽  
Biological Stress ◽  
Evolutionarily Conserved ◽  
Different Types ◽  
Muscle Homeostasis ◽  
Catabolic Process ◽  
Cellular Organelles

Autophagy is an evolutionarily conserved catabolic process that targets different types of cytoplasmic cargo (such as bulk cytoplasm, damaged cellular organelles, and misfolded protein aggregates) for lysosomal degradation. Autophagy is activated in response to biological stress and also plays a critical role in the maintenance of normal cellular homeostasis; the latter function is particularly important for the integrity of postmitotic, metabolically active tissues, such as skeletal muscle. Through impairment of muscle homeostasis, autophagy dysfunction contributes to the pathogenesis of many different skeletal myopathies; the observed autophagy defects differ from disease to disease but have been shown to involve all steps of the autophagic cascade (from induction to lysosomal cargo degradation) and to impair both bulk and selective autophagy. To highlight the molecular and cellular mechanisms that are shared among different myopathies with deficient autophagy, these disorders are discussed based on the nature of the underlying autophagic defect rather than etiology or clinical presentation.

scholarly journals Cardiac progenitor cell sheets secrete proangiogenic growth factors and locally activate capillarogenesis after infarction

2021 ◽  
Vol 10 (3) ◽  
pp. 34-43
Author(s):  
K. V. Dergilev ◽  
Z. I. Tsokolaeva ◽  
Yu. D. Vasilets ◽  
I. B. Beloglazova ◽  
E. V. Parfenova
Keyword(s):  
Myocardial Infarction ◽  
Growth Factors ◽  
Heart Diseases ◽  
Cell Sheet ◽  
Antibody Array ◽  
Matrix Remodeling ◽  
Post Transplantation ◽  
Cell Sheets ◽  
Hypoxic Conditions

Background.      The application of tissue-engineered constructs that simulate the natural microenvironment of cells, maintain their viability and functional properties, is a new promising route for the treatment of ischemic diseases. However, the mechanisms that ensure the effectiveness of this type of treatment and the principles of choosing the optimal population of progenitor cells remain poorly understood.        Aim. To study the profile of secretion of proangiogenic growth factors of cardiosphere-derived cell sheet (CS), and to study the effect of their transplantation on postinfarction myocardial vascularization.            Methods. Assembly of cardiosphere-derived cell sheets were performed on thermosensitive culture plates. Characterization of cell sheets was performed using immunofluorescence staining and a commercial kit for the determination of proangiogenic factors “Mouse Angiogenesis Antibody Array”. The evaluation of the angiogenic properties of the cell graft in vivo was carried out using a rat myocardial infarction model.              Results. It was found that the cardiosphere-derived cell sheet secrete factors involved in the regulation of vasculo-/angiogenesis. At the same time, the cultivation of cell sheets under hypoxic conditions (3% O2) led to an increase in the secretion of proangigenic factors VEGF and pIgF, fGf-1, FGF-2, endothelin-1, as well as MMP-9, which is involved in extracellular matrix remodeling. Cell sheet transplantation on the epicardial surface of the heart after myocardial infarction ensures cell viability and local increase in capillarization of the damaged area. Conclusion. Thus, the application of cardiosphere-derived cell sheets, which have proangiogenic properties and ability to maintain post transplantation cell survival, can be considered as a promising approach for the development of new methods of therapy for heart diseases

scholarly journals Exosomes and Brain Metastases: A Review on Their Role and Potential Applications

2021 ◽  
Vol 22 (19) ◽  
pp. 10899
Author(s):  
Filipa D. Oliveira ◽  
Miguel A. R. B. Castanho ◽  
Vera Neves
Keyword(s):  
Brain Metastases ◽  
Intercellular Communication ◽  
Therapeutic Strategies ◽  
Cancer Therapies ◽  
Life Prognosis ◽  
Potential Applications ◽  
Advanced Stages ◽  
Promising Application

Brain metastases (BM) are a frequent complication in patients with advanced stages of cancer, associated with impairment of the neurological function, quality of life, prognosis, and survival. BM treatment consists of a combination of the available cancer therapies, such as surgery, radiotherapy, chemotherapy, immunotherapy and targeted therapies. Even so, cancer patients with BM are still linked to poor prognosis, with overall survival being reported as 12 months or less. Intercellular communication has a pivotal role in the development of metastases, therefore, it has been extensively studied not only to better understand the metastization process, but also to further develop new therapeutic strategies. Exosomes have emerged as key players in intercellular communication being potential therapeutic targets, drug delivery systems (DDS) or biomarkers. In this Review, we focus on the role of these extracellular vesicles (EVs) in BM formation and their promising application in the development of new BM therapeutic strategies.

scholarly journals Amino Acid Degrading Enzymes and Autophagy in Cancer Therapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Ziyu Wang ◽  
Qinghong Xie ◽  
Haifeng Zhou ◽  
Min Zhang ◽  
Jie Shen ◽  
...  
Keyword(s):  
Amino Acid ◽  
Therapeutic Strategy ◽  
Lymphoblastic Leukemia ◽  
Arginine Deiminase ◽  
Amino Acid Deprivation ◽  
Degrading Enzymes ◽  
Evolutionarily Conserved ◽  
Lysine Oxidase ◽  
Potential Cancer ◽  
Catabolic Process

Recently, there has been renewed interest in metabolic therapy for cancer, particularly in amino acid deprivation by enzymes. L-asparaginase was approved for the treatment of acute lymphoblastic leukemia by the U.S. Food and Drug Administration. Arginine deiminase and recombinant human arginase have been developed into clinical trials as potential cancer therapeutic agents for the treatment of arginine-auxotrophic tumors. Moreover, other novel amino acid degrading enzymes, such as glutaminase, methionase, lysine oxidase, phenylalanine ammonia lyase, have been developed for the treatment of malignant cancers. One of the greatest obstacles faced by anticancer drugs is the development of drug resistance, which is reported to be associated with autophagy. Autophagy is an evolutionarily conserved catabolic process that is responsible for the degradation of dysfunctional proteins and organelles. There is a growing body of literature revealing that, in response to metabolism stress, autophagy could be induced by amino acid deprivation. The manipulation of autophagy in combination with amino acid degrading enzymes is actively being investigated as a potential therapeutic approach in preclinical studies. Importantly, shedding light on how autophagy fuels tumor metabolism during amino acid deprivation will enable more potential combinational therapeutic strategies. This study summarizes recent advances, discussing several potential anticancer enzymes, and highlighting the promising combined therapeutic strategy of amino acid degrading enzymes and autophagy modulators in tumors

scholarly journals CHITINASE-LIKE PROTEINS AS PROMISING MARKERS IN CANCER PATIENTS

2018 ◽  
Vol 17 (4) ◽  
pp. 99-105 ◽  
Author(s):  
I. V. Larionova ◽  
T. N. Sevastyanova ◽  
A. A. Rakina ◽  
N. V. Cherdyntseva ◽  
Ju. G. Kzhyshkowska
Keyword(s):  
Growth Factors ◽  
Cancer Patient ◽  
Cancer Patients ◽  
Inflammatory Diseases ◽  
Tumour Progression ◽  
Patient Benefit ◽  
Pathological Conditions ◽  
The Family ◽  
Metastasis Development

In the present review we collected the main studies regarding the role of chitinase-like proteins (CLPs), belonging to the family of Glyco_18 domain-containing proteins, in different cancers. In  humans, 3 chitinaselike proteins have been identified: YKL-40 (CHI3L1), YKL-39 (CHI3L2) and  stabilin-1-interacting chitinase-like protein (SI-CLP). CLPs are produced by several types of cells  and combine the properties of cytokines and growth factors. The high levels of CLPs were  identified in the circulation of the patients with inflammatory diseases and various types of  tumors. We highlighted the main known functions of CLPs in normal and pathological conditions, their contribution to metastasis development, angiogenesis, invasion and other processes in  cancer, the correlation of the levels of CLPs with tumour progression. Our data also contribute to the understanding of question how CLP could be useful for cancer patient benefit.

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