Cancer is now considered as a heterogeneous ecosystem in which tumor cells collaborate with each other and with host cells in their microenvironment. As circumstances change, the ecosystem evolves to ...ensure the survival and growth of the cancer cells. In this ecosystem, metabolism is not only a key player but also drives stemness. In this review, we first summarize our current understanding of how autophagy influences cancer stem cell phenotype. We emphasize metabolic pathways in cancer stem cells and discuss how autophagy-mediated regulation metabolism is involved in their maintenance and proliferation. We then provide an update on the role of metabolic reprogramming and plasticity in cancer stem cells. Finally, we discuss how metabolic pathways in cancer stem cells could be therapeutically targeted.
Iron is an essential nutrient that facilitates cell proliferation and growth. Iron can be detrimental, however. The ability of iron to cycle between oxidized and reduced forms contributes to the ...formation of free radicals. An excess of free radicals leads to lipid peroxidation, more reactive oxygen species and oxidative stress, damage to DNA and other biomolecules, and, if potentially, tumorigenesis. Iron also has a role in the maintenance of the tumor microenvironment and in metastasis. Pathways of iron acquisition, efflux, storage, and regulation are all perturbed in cancer, suggesting that reprogramming of iron metabolism is a central aspect of tumor cell survival. Recent studies have shed light on the role of iron metabolism in cancer stem cells (CSC) and suggest that specific targeting of iron metabolism in CSCs may improve the efficacy of cancer therapy. In this review, we first summarize briefly our current understanding of the intracellular processes involving iron, the effect of dietary iron, and its relation to cancer. We emphasize the importance of modifier “iron genes” in cancer and the possibility that these genes may encode biomarkers that may be used clinically. We then provide an update on the role of iron in metabolic reprogramming, the epithelial-mesenchymal transition, and the regulation of epigenetic marks essential for CSC maintenance and plasticity. Finally, we discuss the potential of targeting a recently discovered form of iron-regulated cell death, ferroptosis, in CSCs for treatment of cancer.
Autophagy: A Druggable Process Morel, Etienne; Mehrpour, Maryam; Botti, Joëlle ...
Annual review of pharmacology and toxicology,
01/2017, Letnik:
57, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Macroautophagy (hereafter called autophagy) is a vacuolar, lysosomal pathway for catabolism of intracellular material that is conserved among eukaryotic cells. Autophagy plays a crucial role in ...tissue homeostasis, adaptation to stress situations, immune responses, and the regulation of the inflammatory response. Blockade or uncontrolled activation of autophagy is associated with cancer, diabetes, obesity, cardiovascular disease, neurodegenerative disease, autoimmune disease, infection, and chronic inflammatory disease. During the past decade, researchers have made major progress in understanding the three levels of regulation of autophagy in mammalian cells: signaling, autophagosome formation, and autophagosome maturation and lysosomal degradation. As we discuss in this review, each of these levels is potentially druggable, and, depending on the indication, may be able to stimulate or inhibit autophagy. We also summarize the different modulators of autophagy and their potential and limitations in the treatment of life-threatening diseases.
Autophagy regulation and its role in cancer Lorin, Séverine; Hamaï, Ahmed; Mehrpour, Maryam ...
Seminars in cancer biology,
10/2013, Letnik:
23, Številka:
5
Journal Article
Recenzirano
Abstract The modulation of macroautophagy is now recognized as one of the hallmarks of cancer cells. There is accumulating evidence that autophagy plays a role in the various stages of tumorigenesis. ...Depending on the type of cancer and the context, macroautophagy can be tumor suppressor or it can help cancer cells to overcome metabolic stress and the cytotoxicity of chemotherapy. Recent studies have shed light on the role of macroautophagy in tumor-initiating cells, in tumor immune response cross-talk with the microenvironment. This review is intended to provide an up-date on these aspects, and to discuss them with regard to the role of the major signaling sub-networks involved in tumor progression (Beclin 1, MTOR, p53 and RAS) and in regulating autophagy.
Cancer stem cells (CSCs) are a distinct subpopulation of tumor cells with stem cell-like features. Able to initiate and sustain tumor growth and mostly resistant to anti-cancer therapies, they are ...thought responsible for tumor recurrence and metastasis. Recent accumulated evidence supports that iron metabolism with the recent discovery of ferroptosis constitutes a promising new lead in the field of anti-CSC therapeutic strategies. Indeed, iron uptake, efflux, storage and regulation pathways are all over-engaged in the tumor microenvironment suggesting that the reprogramming of iron metabolism is a crucial occurrence in tumor cell survival. In particular, recent studies have highlighted the importance of iron metabolism in the maintenance of CSCs. Furthermore, the high concentration of iron found in CSCs, as compared to non-CSCs, underlines their iron addiction. In line with this, if iron is an essential macronutrient that is nevertheless highly reactive, it represents their Achilles' heel by inducing ferroptosis cell death and therefore providing opportunities to target CSCs. In this review, we first summarize our current understanding of iron metabolism and its regulation in CSCs. Then, we provide an overview of the current knowledge of ferroptosis and discuss the role of autophagy in the (regulation of) ferroptotic pathways. Finally, we discuss the potential therapeutic strategies that could be used for inducing ferroptosis in CSCs to treat cancer.
Breast cancer tissue contains a small population of cells that have the ability to self-renew; these cells are known as cancer stem-like cells (CSCs). We have recently shown that autophagy is ...essential for the tumorigenicity of these CSCs. Salinomycin (Sal), a K
+
/H
+
ionophore, has recently been shown to be at least 100 times more effective than paclitaxel in reducing the proportion of breast CSCs. However, its mechanisms of action are still unclear. We show here that Sal blocked both autophagy flux and lysosomal proteolytic activity in both CSCs and non-CSCs derived from breast cancer cells. GFP-LC3 staining combined with fluorescent dextran uptake and LysoTracker-Red staining showed that autophagosome/lysosome fusion was not altered by Sal treatment. Acridine orange staining provided evidence that lysosomes display the characteristics of acidic compartments in Sal-treated cells. However, tandem mCherry-GFP-LC3 assay indicated that the degradation of mCherry-GFP-LC3 is blocked by Sal. Furthermore, the protein degradation activity of lysosomes was inhibited, as demonstrated by the rate of long-lived protein degradation, DQ-BSA assay and measurement of cathepsin activity. Our data indicated that Sal has a relatively greater suppressant effect on autophagic flux in the ALDH
+
population in HMLER cells than in the ALDH
−
population; moreover, this differential effect on autophagic flux correlated with an increase in apoptosis in the ALDH
+
population. ATG7 depletion accelerated the proapoptotic capacity of Sal in the ALDH
+
population. Our findings provide new insights into how the autophagy-lysosomal pathway contributes to the ability of Sal to target CSCs in vitro.
Recent advances highlight that non-coding RNAs (ncRNAs) are emerging as fundamental regulators in various physiological as well as pathological processes by regulating macro-autophagy. Studies have ...disclosed that macro-autophagy, which is a highly conserved process involving cellular nutrients, components, and recycling of organelles, can be either selective or non-selective and ncRNAs show their regulation on selective autophagy as well as non-selective autophagy. The abnormal expression of ncRNAs will result in the impairment of autophagy and contribute to carcinogenesis and cancer progression by regulating both selective autophagy as well as non-selective autophagy. This review focuses on the regulatory roles of ncRNAs in autophagy and their involvement in cancer which may provide valuable therapeutic targets for cancer management.
•The article revises non-coding RNAs (ncRNAs) as new autophagy regulators in carcinogenesis and cancer progression.•Both selective and non-selective autophagy emerge as a double-edged sword in caner.•Therapeutic approaches resversing the abnormal expression of autophagy-related ncRNAs are promising
(1) Background: Triple-negative breast cancer (TNBC) is a distinct subgroup of breast cancer presenting a high level of recurrence, and neo-adjuvant chemotherapy is beneficial in its therapy ...management. Anti-PD-L1 immunotherapy improves the effect of neo-adjuvant therapy in TNBC. (2) Methods: Immune-modulation and ferroptosis-related R-packages were developed for integrative omics analyses under ferroptosis-inducer treatments: TNBC cells stimulated with ferroptosis inducers (GSE173905, GSE154425), single cell data (GSE191246) and mass spectrometry on breast cancer stem cells. Clinical association analyses were carried out with breast tumors (TCGA and METABRIC cohorts). Protein-level validation was investigated through protein atlas proteome experiments. (3) Results: Erastin/RSL3 ferroptosis inducers upregulate CD274 in TNBC cells (MDA-MB-231 and HCC38). In breast cancer, CD274 expression is associated with overall survival. Breast tumors presenting high expression of CD274 upregulated some ferroptosis drivers associated with prognosis: IDO1, IFNG and TNFAIP3. At the protein level, the induction of Cd274 and Tnfaip3 was confirmed in breast cancer stem cells under salinomycin treatment. In a 4T1 tumor treated with cyclophosphamide, the single cell expression of Cd274 was found to increase both in myeloid- and lymphoid-infiltrated cells, independently of its receptor Pdcd1. The CD274 ferroptosis-driver score computed on a breast tumor transcriptome stratified patients on their prognosis: low score was observed in the basal subgroup, with a higher level of recurrent risk scores (oncotypeDx, ggi and gene70 scores). In the METABRIC cohort, CD274, IDO1, IFNG and TNFAIP3 were found to be overexpressed in the TNBC subgroup. The CD274 ferroptosis-driver score was found to be associated with overall survival, independently of TNM classification and age diagnosis. The tumor expression of CD274, TNFAIP3, IFNG and IDO1, in a biopsy of breast ductal carcinoma, was confirmed at the protein level (4) Conclusions: Ferroptosis inducers upregulate PD-L1 in TNBC cells, known to be an effective target of immunotherapy in high-risk early TNBC patients who received neo-adjuvant therapy. Basal and TNBC tumors highly expressed CD274 and ferroptosis drivers: IFNG, TNFAIP3 and IDO1. The CD274 ferroptosis-driver score is associated with prognosis and to the risk of recurrence in breast cancer. A potential synergy of ferroptosis inducers with anti-PD-L1 immunotherapy is suggested for recurrent TNBC.
Macroautophagy is an evolutionarily conserved homeostatic process that mediates the degradation of long-lived cytoplasmic components in eukaryotes, which allows cells to survive stresses such as ...inflammation, hypoxia, and deprivation of nutrients or growth factors. At least 30 members of the Atg (autophagy-related) protein family orchestrate this degradative process. Additional complexity resides in the signaling networks controlling the autophagic process, which include various posttranslational modifications of key components. Evidence is accumulating that protein acetylation represents an evolutionarily conserved mechanism tightly regulating macroautophagy.
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