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CMA activity controls the cell cycle and cancer. (A) In physiological conditions, CMA controls the levels of both positive (e.g., MYC and Cyclin D1) and negative (e.g., RDN3, CHK1, and HIF-1α) cell cycle regulators. (B) With low CMA activity, CIP2A and MDM2 are not degraded, which consequently increases the levels of MYC and decreases those of p53, promoting high proliferation and an increase in genetic instability. (C) High CMA activity leads to excessive degradation of the negative regulators of the cell cycle under stressful conditions (CHK1, HIF-1α, and RND3), leading to disorderly growth. (B,C) Therefore, both scenarios (downregulation or upregulation of CMA) can result in malignancy. Figure created with Biorender.
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The cell cycle involves a network of proteins that modulate the sequence and timing of proliferation events. Unregulated proliferation is the most fundamental hallmark of cancer; thus, changes in cell cycle control are at the heart of malignant transformation processes. Several cellular processes can interfere with the cell cycle, including autopha...
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Initially described as lytic bodies due to their degradative and recycling functions, lysosomes play a critical role in metabolic adaptation to nutrient availability. More recently, the contribution of lysosomal proteins to cell signaling has been established, and lysosomes have emerged as signaling hubs that regulate diverse cellular processes, in...
Citations
... CMA activity has been related to both an increase and a reduction in disease. In general, proteolytic mechanisms fail in neurodegenerative diseases, resulting in the buildup of harmful protein transformation (Andrade-Tomaz et al., 2020;Liao et al., 2021). Xu et al. 2021 define Metformin's method of CMA induction as stimulation of TAK1-IKK signaling, which leads to phosphorylation of Ser85 of the central mediator of CMA, Hsc70, and its activation. ...
Introduction: Multiple sclerosis (MS), an autoimmune condition of the central nervous system (CNS), can lead to demyelination and axonal degeneration in the brain and spinal cord, which can cause progressive neurologic disability. MS symptoms include autonomic dysfunction, such as insomnia, neuropathic and nociceptive pain, cognitive impairment, spasticity, dysesthesia, anxiety, and depression, significantly reducing patient quality of life. These symptoms appear in addition to the progressive decline in the nervous system's motor abilities. In this investigation, we performed an integrated bioinformatics and experimental approach to find the expression level and interaction of a novel long non-coding RNA (lncRNA), PAN3-AS1, in MS samples.
Methods: Microarray analysis was performed by R Studio using GEOquery and limma packages. lncRNA-mRNA RNA interaction analysis was performed using the lncRRIsearch database. Pathway enrichment analysis was performed by KEGG and Reactome online software through the Enrichr database. Protein-protein interaction analysis was performed by STRING online software. Gene ontology (GO) analysis was performed by Enrichr database.
Results: Based on microarray analysis, lncRNA PAN3-AS1 has a significantly low expression in MS samples compared to the control (logFC: -1.2, adj. P. Val: 0.03). qRT-PCR results approved bioinformatics analyses. ROC analysis revealed that PAN3-AS1 could be considered a potential diagnostic biomarker of MS. Based on lncRNA-mRNA interaction analysis, lncRNA PAN3-AS1 regulates the expression level of RPGR. RPGR and its protein interactome regulate the cilium assembly, chaperon-mediated autophagy, and microRNA biogenesis.
Conclusion: lncRNA PAN3-AS1, as a significant low-expressed lncRNA in MS samples, could be a potential diagnostic MS biomarker. PAN3-AS1 might regulate the expression level of cilium assembly and chaperon-mediated autophagy. Dysregulation of PAN3-AS1 might affect the expression of RPGR and its protein interactome.
... Notably, elevated levels of LAMP2A have been associated with poor survival rates in non-small cell lung cancer (NSCLC) (Ichikawa et al., 2020). The blockade of CMA has been identified as a key driver of resistance, primarily due to its involvement in the modulation of several factors involved in the regulation of transcription, translation, and cell cycle control (Andrade-Tomaz et al., 2020). Consequently, managing the CMA pathway may hold promise as a therapeutic approach, particularly for patients who are ineligible for surgery and depend only on chemotherapy and radiotherapy. ...
In the search for alternatives to overcome the challenge imposed by drug resistance development in cancer treatment, the modulation of autophagy has emerged as a promising alternative that has achieved good results in clinical trials. Nevertheless, most of these studies have overlooked a novel and selective type of autophagy: chaperone-mediated autophagy (CMA). Following its discovery, research into CMA’s contribution to tumor progression has accelerated rapidly. Therefore, we now understand that stress conditions are the primary signal responsible for modulating CMA in cancer cells. In turn, the degradation of proteins by CMA can offer important advantages for tumorigenesis, since tumor suppressor proteins are CMA targets. Such mutual interaction between the tumor microenvironment and CMA also plays a crucial part in establishing therapy resistance, making this discussion the focus of the present review. Thus, we highlight how suppression of LAMP2A can enhance the sensitivity of cancer cells to several drugs, just as downregulation of CMA activity can lead to resistance in certain cases. Given this panorama, it is important to identify selective modulators of CMA to enhance the therapeutic response.
... Autophagy is an evolutionarily conserved catabolic process that parcels cytoplasmic proteins and damaged or senescent organelles into vesicles, which eventually fuse with lysosomes to form autophagy lysosomes for further degradation [9]. An increasing body of evidence has established the complex regulatory relationship between autophagy and cell cycle arrest in various cancer types [10,11]. However, whether D-arabinose impaired growth by regulating cell cycle via induction of autophagy in breast cancer has not been studied. ...
Breast cancer patients often have a poor prognosis largely due to lack of effective targeted therapy. It is now well established that monosaccharide enhances growth retardation and chemotherapy sensitivity in tumor cells. However, Pectinose whether has capability to restrict the proliferation of tumor cells remain unclear. Here, we report that Pectinose induced cytotoxicity is modulated by autophagy and p38 MAPK signaling pathway in breast cancer cell lines. The proliferation of cells was dramatically inhibited by Pectinose exposure in a dose-dependent manner, which was relevant to cell cycle arrest, as demonstrated by G2/M cell cycle restriction and ectopic expression of Cyclin A, Cyclin B, p21and p27. Mechanistically, we further identified that Pectinose is positively associated with autophagy and the activation of the p38 MAPK signaling in breast cancer. In contrast, 3-Ma or SB203580, the inhibitor of autophagy or p38 MAPK, reversed the efficacy of Pectinose suppressing on breast cancer cell lines proliferation and cell cycle process. Additionally, Pectinose in vivo treatment could significantly inhibit xenograft growth of breast cancer cells. Taken together, our findings were the first to reveal that Pectinose triggered cell cycle arrest by inducing autophagy through the activation of p38 MAPK signaling pathway in breast cancer cells,especially in luminal A and triple-negative breast cancer.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12885-024-12293-8.
... In contrast, microautophagy, a nonselective lysosomal degradative pathway, directly engulfs portions of the cytoplasmic material through the lysosomal membrane via invagination [6]. CMA selectively recognizes specific motifs in cytosolic substrates and targets them for lysosomal degradation [7]. Molecular chaperone heat shock cognate protein 70 (Hsc70) targets the substrates with KFERQ-like motifs to the lysosomal membrane [8]. ...
Autophagy is an intracellular recycling process that maintains cellular homeostasis by degrading excess or defective macromolecules and organelles. Chaperone-mediated autophagy (CMA) is a highly selective form of autophagy in which a substrate containing a KFERQ-like motif is recognized by a chaperone protein, delivered to the lysosomal membrane, and then translocated to the lysosome for degradation with the assistance of lysosomal membrane protein 2A. Normal CMA activity is involved in the regulation of cellular proteostasis, metabolism, differentiation, and survival. CMA dysfunction disturbs cellular homeostasis and directly participates in the pathogenesis of human diseases. Previous investigations on CMA in the central nervous system have primarily focus on neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease. Recently, mounting evidence suggested that brain injuries involve a wider range of types and severities, making the involvement of CMA in the bidirectional processes of damage and repair even more crucial. In this review, we summarize the basic processes of CMA and its associated regulatory mechanisms and highlight the critical role of CMA in brain injury such as cerebral ischemia, traumatic brain injury, and other specific brain injuries. We also discuss the potential of CMA as a therapeutic target to treat brain injury and provide valuable insights into clinical strategies.
Graphical Abstract
... www.nature.com/scientificreports/ autophagy and cell cycle arrest in various cancer types 10,11 . However, whether d-arabinose impaired growth by regulating cell cycle via induction of autophagy in breast cancer has not been studied. ...
Breast cancer patients often have a poor prognosis largely due to lack of effective targeted therapy. It is now well established that monosaccharide enhances growth retardation and chemotherapy sensitivity in tumor cells. We investigated whether d-arabinose has capability to restrict the proliferation of tumor cells and its mechanism. Here, we report that d-arabinose induced cytotoxicity is modulated by autophagy and p38 MAPK signaling pathway in breast cancer cell lines. The proliferation of cells was evaluated by CCK-8 and Colony formation assay. The distribution of cells in cell cycle phases was analyzed by flow cytometry. Cell cycle, autophagy and MAPK signaling related proteins were detected by western blotting. Mouse xenograft model was used to evaluate the efficacy of d-arabinose in vivo. The proliferation of cells was dramatically inhibited by d-arabinose exposure in a dose-dependent manner, which was relevant to cell cycle arrest, as demonstrated by G2/M cell cycle restriction and ectopic expression of cell cycle related proteins. Mechanistically, we further identified that d-arabinose is positively associated with autophagy and the activation of the p38 MAPK signaling in breast cancer. In contrast, 3-Ma or SB203580, the inhibitor of autophagy or p38 MAPK, reversed the efficacy of d-arabinose. Additionally, d-arabinose in vivo treatment could significantly inhibit xenograft growth of breast cancer cells. Our findings were the first to reveal that d-arabinose triggered cell cycle arrest by inducing autophagy through the activation of p38 MAPK signaling pathway in breast cancer cells.
... According to the mechanism used to deliver cargo to the lysosome, autophagy can be categorized as macroautophagy, microautophagy and CMA [46]. To decipher whether macroautophagy is the mechanism involved in HIF-1α degradation, classical markers of macroautophagy were checked in HeLa cells [47]. ...
ALKBH1 is a typical demethylase of nucleic acids, which is correlated with multiple types of biological processes and human diseases. Recent studies are focused on the demethylation of ALKBH1, but little is known about its non-demethylase function. Here, we demonstrate that ALKBH1 regulates the glycolysis process through HIF-1α signaling in a demethylase-independent manner. We observed that depletion of ALKBH1 inhibits glycolysis flux and extracellular acidification, which is attributable to reduced HIF-1α protein levels, and it can be rescued by reintroducing HIF-1α. Mechanistically, ALKBH1 knockdown enhances chaperone-mediated autophagy (CMA)-mediated HIF-1α degradation by facilitating the interaction between HIF-1α and LAMP2A. Furthermore, we identify that ALKBH1 competitively binds to the OST48, resulting in compromised structural integrity of oligosaccharyltransferase (OST) complex and subsequent defective N-glycosylation of LAMPs, particularly LAMP2A. Abnormal glycosylation of LAMP2A disrupts lysosomal homeostasis and hinders the efficient degradation of HIF-1α through CMA. Moreover, NGI-1, a small-molecule inhibitor that selectively targets the OST complex, could inhibit the glycosylation of LAMPs caused by ALKBH1 silencing, leading to impaired CMA activity and disruption of lysosomal homeostasis. In conclusion, we have revealed a non-demethylation role of ALKBH1 in regulating N-glycosylation of LAMPs by interacting with OST subunits and CMA-mediated degradation of HIF-1α.
... Chaperone-mediated autophagy (CMA) is a selective form of autophagy that targets specific individual proteins for degradation [28,29]. CMA involves cytosolic proteins with KFERQ-like motifs that are recognized by chaperone HSC70, and these proteins are delivered to the lysosomal-associated membrane protein 2A (LAMP2A), which allows for the translocation of these proteins into the lysosome for degradation [30]. Quite a few proteins involved in neurodegenerative disorders, including α-synuclein [31-33] and β-amyloid precursor protein [32], contain this motif. ...
Autophagy is a vital cellular process that functions to degrade and recycle damaged organelles into basic metabolites. This allows a cell to adapt to a diverse range of challenging conditions. Autophagy assists in maintaining homeostasis, and it is tightly regulated by the cell. The disruption of autophagy has been associated with many diseases, such as neurodegenerative disorders and cancer. This review will center its discussion on providing an in-depth analysis of the current molecular understanding of autophagy and its relevance to brain tumors. We will delve into the current literature regarding the role of autophagy in glioma pathogenesis by exploring the major pathways of JAK2/STAT3 and PI3K/AKT/mTOR and summarizing the current therapeutic interventions and strategies for glioma treatment. These treatments will be evaluated on their potential for autophagy induction and the challenges associated with their utilization. By understanding the mechanism of autophagy, clinical applications for future therapeutics in treating gliomas can be better targeted.
... Furthermore, the levels of the proto-oncogenic protein MDM2 and the tumor-associated protein TCTP can also be controlled by CMA [36,37]. The role of CMA in cell cycle control and anti-tumor function has recently been reviewed and discussed by Andrade-Tomaz et al. [38]. ...
Incidence of cancer is markedly reduced in patients with the hereditary neurodegenerative polyglutamine (polyQ) diseases. We have very poor knowledge of the underlying molecular mechanisms, but the expanded polyQ sequence is assumed to play a central role, because it is common to the respective disease related proteins. The inhibition seems to take place in all kinds of cells, because the lower cancer frequency applies to nearly all types of tumors and is not related with the characteristic pathological changes in specific brain tissues. Further, the cancer repressing mechanisms appear to be active early in life including in pre-symptomatic and early phase polyQ patients. Autophagy plays a central role in clearing proteins with expanded polyQ tracts, and autophagy modulation has been demonstrated and particularly investigated in Huntington’s disease (HD). Macroautophagy may be dysfunctional due to defects in several steps of the process, whereas increased chaperone-mediated autophagy (CMA) has been shown in HD patients, cell and animal models. Recently, CMA is assumed to play a key role in prevention of cellular transformation of normal cells into cancer cells. Investigations of normal cells from HD and other polyQ carriers could therefore add further insight into the protective mechanisms of CMA in tumorigenesis, and be important for development of autophagy based strategies to prevent malignant processes leading to cancer and neurodegeneration.
... Firstly, the autophagy-dependent cell cycle and death were not investigated in this study. Recently, autophagy was reported to play an important regulatory role in cell cycle and death in cancer cells [41,42]. Wu et al. [43] found an inverse correlation between autophagy and cyclin D1, one checkpoint of cell cycle, in hepatocellular carcinoma, and activated autophagy could selectively degrade cyclin D1, which in turn suppressing cell proliferation via the cell cycle arrest at the G1 phase. ...
COTE1 was recently described as an oncogene in hepatocellular carcinoma and gastric cancer. However, the roles of COTE1 in intrahepatic cholangiocarcinoma (ICC) are little known. Our study is aimed at clarifying novel functions of COTE1 in ICC progression, including proliferation, invasion, and autophagy. By using quantitative real-time PCR, immunohistochemistry staining, and western blotting, we found that COTE1 expression was frequently upregulated in ICC tissues, compared to paracarcinoma tissues. High COTE1 expression was significantly correlated with aggressive clinical features and predicted poor prognosis of ICC patients. Functional experiments revealed that ectopic COTE1 expression promoted ICC cell proliferation, colony formation, cellular invasion, migration, and in vivo tumorigenicity; in contrast, COTE1 knockdown resulted in the opposite effects. At molecular mechanism in vitro and vivo, our study revealed that COTE1 overexpression suppressed autophagy via Beclin1 transcription inhibition; conversely, COTE1 silencing facilitated autophagy through promoting Beclin1 expression. Furthermore, the suppression of COTE1 knockdown on cellular growth and invasion was rescued/aggravated by Beclin1 inhibition/accumulation. Our data, for the first time, illustrate that COTE1 is an oncogene in ICC pathogenesis, and the ectopic COTE1 expression promotes ICC proliferation and invasion via Beclin1-dependent autophagy inhibition.
... In tumors, the effects of CMA are much more complex, as both positive and negative regulators may undergo degradation as CMA substrates, and it remains to be fully explored to investigate the role of CMA overactivation or inhibition in tumor promotion. 105 ...
Chaperone‐mediated autophagy (CMA) is a lysosomal degradation pathway that eliminates substrate proteins through heat‐shock cognate protein 70 recognition and lysosome‐associated membrane protein type 2A‐assisted translocation. It is distinct from macroautophagy and microautophagy. In recent years, the regulatory mechanisms of CMA have been gradually enriched, including the newly discovered NRF2 and p38–TFEB signaling, as positive and negative regulatory pathways of CMA, respectively. Normal CMA activity is involved in the regulation of metabolism, aging, immunity, cell cycle, and other physiological processes, while CMA dysfunction may be involved in the occurrence of neurodegenerative disorders, tumors, intestinal disorders, atherosclerosis, and so on, which provides potential targets for the treatment and prediction of related diseases. This article describes the general process of CMA and its role in physiological activities and summarizes the connection between CMA and macroautophagy. In addition, human diseases that concern the dysfunction or protective role of CMA are discussed. Our review deepens the understanding of the mechanisms and physiological functions of CMA and provides a summary of past CMA research and a vision of future directions.
