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1.
Targeting autophagy in prostate cancer: preclinical and clinical evidence for therapeutic response.
Ashrafizadeh, M, Paskeh, MDA, Mirzaei, S, Gholami, MH, Zarrabi, A, Hashemi, F, Hushmandi, K, Hashemi, M, Nabavi, N, Crea, F, et al
Journal of experimental & clinical cancer research : CR. 2022;(1):105
Abstract
Prostate cancer is a leading cause of death worldwide and new estimates revealed prostate cancer as the leading cause of death in men in 2021. Therefore, new strategies are pertinent in the treatment of this malignant disease. Macroautophagy/autophagy is a "self-degradation" mechanism capable of facilitating the turnover of long-lived and toxic macromolecules and organelles. Recently, attention has been drawn towards the role of autophagy in cancer and how its modulation provides effective cancer therapy. In the present review, we provide a mechanistic discussion of autophagy in prostate cancer. Autophagy can promote/inhibit proliferation and survival of prostate cancer cells. Besides, metastasis of prostate cancer cells is affected (via induction and inhibition) by autophagy. Autophagy can affect the response of prostate cancer cells to therapy such as chemotherapy and radiotherapy, given the close association between autophagy and apoptosis. Increasing evidence has demonstrated that upstream mediators such as AMPK, non-coding RNAs, KLF5, MTOR and others regulate autophagy in prostate cancer. Anti-tumor compounds, for instance phytochemicals, dually inhibit or induce autophagy in prostate cancer therapy. For improving prostate cancer therapy, nanotherapeutics such as chitosan nanoparticles have been developed. With respect to the context-dependent role of autophagy in prostate cancer, genetic tools such as siRNA and CRISPR-Cas9 can be utilized for targeting autophagic genes. Finally, these findings can be translated into preclinical and clinical studies to improve survival and prognosis of prostate cancer patients.
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2.
Non-coding RNAs as new autophagy regulators in cancer progression.
Lin, Q, Shi, Y, Liu, Z, Mehrpour, M, Hamaï, A, Gong, C
Biochimica et biophysica acta. Molecular basis of disease. 2022;(1):166293
Abstract
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.
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3.
Lipid Droplets and Their Autophagic Turnover via the Raft-Like Vacuolar Microdomains.
Rahman, MA, Kumar, R, Sanchez, E, Nazarko, TY
International journal of molecular sciences. 2021;(15)
Abstract
Although once perceived as inert structures that merely serve for lipid storage, lipid droplets (LDs) have proven to be the dynamic organelles that hold many cellular functions. The LDs' basic structure of a hydrophobic core consisting of neutral lipids and enclosed in a phospholipid monolayer allows for quick lipid accessibility for intracellular energy and membrane production. Whereas formed at the peripheral and perinuclear endoplasmic reticulum, LDs are degraded either in the cytosol by lipolysis or in the vacuoles/lysosomes by autophagy. Autophagy is a regulated breakdown of dysfunctional, damaged, or surplus cellular components. The selective autophagy of LDs is called lipophagy. Here, we review LDs and their degradation by lipophagy in yeast, which proceeds via the micrometer-scale raft-like lipid domains in the vacuolar membrane. These vacuolar microdomains form during nutrient deprivation and facilitate internalization of LDs via the vacuolar membrane invagination and scission. The resultant intra-vacuolar autophagic bodies with LDs inside are broken down by vacuolar lipases and proteases. This type of lipophagy is called microlipophagy as it resembles microautophagy, the type of autophagy when substrates are sequestered right at the surface of a lytic compartment. Yeast microlipophagy via the raft-like vacuolar microdomains is a great model system to study the role of lipid domains in microautophagic pathways.
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4.
Autophagy and Extracellular Vesicles, Connected to rabGTPase Family, Support Aggressiveness in Cancer Stem Cells.
Brunel, A, Bégaud, G, Auger, C, Durand, S, Battu, S, Bessette, B, Verdier, M
Cells. 2021;(6)
Abstract
Even though cancers have been widely studied and real advances in therapeutic care have been made in the last few decades, relapses are still frequently observed, often due to therapeutic resistance. Cancer Stem Cells (CSCs) are, in part, responsible for this resistance. They are able to survive harsh conditions such as hypoxia or nutrient deprivation. Autophagy and Extracellular Vesicles (EVs) secretion are cellular processes that help CSC survival. Autophagy is a recycling process and EVs secretion is essential for cell-to-cell communication. Their roles in stemness maintenance have been well described. A common pathway involved in these processes is vesicular trafficking, and subsequently, regulation by Rab GTPases. In this review, we analyze the role played by Rab GTPases in stemness status, either directly or through their regulation of autophagy and EVs secretion.
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5.
Reactive Oxygen Species as a Link between Antioxidant Pathways and Autophagy.
Li, D, Ding, Z, Du, K, Ye, X, Cheng, S
Oxidative medicine and cellular longevity. 2021;:5583215
Abstract
Reactive oxygen species (ROS) are highly reactive molecules that can oxidize proteins, lipids, and DNA. Under physiological conditions, ROS are mainly generated in the mitochondria during aerobic metabolism. Under pathological conditions, excessive ROS disrupt cellular homeostasis. High levels of ROS result in severe oxidative damage to the cellular machinery. However, a low/mild level of ROS could serve as a signal to trigger cell survival mechanisms. To prevent and cope with oxidative damage to biomolecules, cells have developed various antioxidant and detoxifying mechanisms. Meanwhile, ROS can initiate autophagy, a process of self-clearance, which helps to reduce oxidative damage by engulfing and degrading oxidized substance. This review summarizes the interactions among ROS, autophagy, and antioxidant pathways. The effects of natural phytochemicals on autophagy induction, antioxidation, and dual-function are also discussed.
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6.
Heme Oxgenase-1, a Cardinal Modulator of Regulated Cell Death and Inflammation.
Ryter, SW
Cells. 2021;(3)
Abstract
Heme oxygenase catalyzes the rate-limiting step in heme degradation in order to generate biliverdin, carbon monoxide (CO), and iron. The inducible form of the enzyme, heme oxygenase-1 (HO-1), exerts a central role in cellular protection. The substrate, heme, is a potent pro-oxidant that can accelerate inflammatory injury and promote cell death. HO-1 has been implicated as a key mediator of inflammatory cell and tissue injury, as validated in preclinical models of acute lung injury and sepsis. A large body of work has also implicated HO-1 as a cytoprotective molecule against various forms of cell death, including necrosis, apoptosis and newly recognized regulated cell death (RCD) programs such as necroptosis, pyroptosis, and ferroptosis. While the antiapoptotic potential of HO-1 and its reaction product CO in apoptosis regulation has been extensively characterized, relatively fewer studies have explored the regulatory role of HO-1 in other forms of necrotic and inflammatory RCD (i.e., pyroptosis, necroptosis and ferroptosis). HO-1 may provide anti-inflammatory protection in necroptosis or pyroptosis. In contrast, in ferroptosis, HO-1 may play a pro-death role via enhancing iron release. HO-1 has also been implicated in co-regulation of autophagy, a cellular homeostatic program for catabolic recycling of proteins and organelles. While autophagy is primarily associated with cell survival, its occurrence can coincide with RCD programs. This review will summarize the roles of HO-1 and its reaction products in co-regulating RCD and autophagy programs, with its implication for both protective and detrimental tissue responses, with emphasis on how these impact HO-1 as a candidate therapeutic target in disease.
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7.
Collagen metabolism as a regulator of proline dehydrogenase/proline oxidase-dependent apoptosis/autophagy.
Palka, J, Oscilowska, I, Szoka, L
Amino acids. 2021;(12):1917-1925
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Abstract
Recent studies on the regulatory role of amino acids in cell metabolism have focused on the functional significance of proline degradation. The process is catalysed by proline dehydrogenase/proline oxidase (PRODH/POX), a mitochondrial flavin-dependent enzyme converting proline into ∆1-pyrroline-5-carboxylate (P5C). During this process, electrons are transferred to electron transport chain producing ATP for survival or they directly reduce oxygen, producing reactive oxygen species (ROS) inducing apoptosis/autophagy. However, the mechanism for switching survival/apoptosis mode is unknown. Although PRODH/POX activity and energetic metabolism were suggested as an underlying mechanism for the survival/apoptosis switch, proline availability for this enzyme is also important. Proline availability is regulated by prolidase (proline supporting enzyme), collagen biosynthesis (proline utilizing process) and proline synthesis from glutamine, glutamate, α-ketoglutarate (α-KG) and ornithine. Proline availability is dependent on the rate of glycolysis, TCA and urea cycles, proline metabolism, collagen biosynthesis and its degradation. It is well established that proline synthesis enzymes, P5C synthetase and P5C reductase as well as collagen prolyl hydroxylases are up-regulated in most of cancer types and control rates of collagen biosynthesis. Up-regulation of collagen prolyl hydroxylase and its exhaustion of ascorbate and α-KG may compete with DNA and histone demethylases (that require the same cofactors) to influence metabolic epigenetics. This knowledge led us to hypothesize that up-regulation of prolidase and PRODH/POX with inhibition of collagen biosynthesis may represent potential pharmacotherapeutic approach to induce apoptosis or autophagic death in cancer cells. These aspects of proline metabolism are discussed in the review as an approach to understand complex regulatory mechanisms driving PRODH/POX-dependent apoptosis/survival.
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8.
Non-coding RNA-mediated autophagy in cancer: A protumor or antitumor factor?
Liang, J, Zhang, L, Cheng, W
Biochimica et biophysica acta. Reviews on cancer. 2021;(2):188642
Abstract
Autophagy, usually referred to as macroautophagy, is a cytoprotective behavior that helps cells, especially cancer cells, escape crises. However, the role of autophagy in cancer remains controversial. The induction of autophagy is favorable for tumor growth, as it can degrade damaged cell components accumulated during nutrient deficiency, chemotherapy, or other stresses in a timely manner. Whereas the antitumor effect of autophagy might be closely related to its crosstalk with metabolism, immunomodulation, and other pathways. Recent studies have verified that lncRNAs and circRNAs modulate autophagy in carcinogenesis, cancer cells proliferation, apoptosis, metastasis, and chemoresistance via multiple mechanisms. A comprehensive understanding of the regulatory relationships between ncRNAs and autophagy in cancer might resolve chemoresistance and also offer intervention strategies for cancer therapy. This review systematically displays the regulatory effects of lncRNAs and circRNAs on autophagy in the contexts of cancer initiation, progression, and resistance to chemo- or radiotherapy and provides a novel insight into cancer therapy.
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9.
Ubiquitin pathways regulate the pathogenesis of chronic liver disease.
Park, JS, Ma, H, Roh, YS
Biochemical pharmacology. 2021;:114764
Abstract
Chronic liver disease (CLD) is considered the leading cause of global mortality. In westernized countries, increased consumption of alcohol and overeating foods with high fat/ high glucose promote progression of CLD such as alcoholic liver disease (ALD) and non-alcoholic liver disease (NAFLD). Accumulating evidence and research suggest that ubiquitin, a 75 amino acid protein, plays crucial role in the pathogenesis of CLD through dynamic post-translational modifications (PTMs) exerting diverse cellular outcomes such as protein degradation through ubiquitin-proteasome system (UPS) and autophagy, and regulation of signal transduction. In this review, we present the function of ubiquitination and latest findings on diverse mechanism of PTMs, UPS and autophagy which significantly contribute to the pathogenesis of alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), cirrhosis, and HCC. Despite its high prevalence, morbidity, and mortality, there are only few FDA approved drugs that could be administered to CLD patients. The goal of this review is to present a variety of pathways and therapeutic targets involving ubiquitination in the pathogenesis of CLD. Further, this review summarizes collective views of pharmaceutical inhibition or activation of recent drugs targeting UPS and autophagy system to highlight potential targets and new approaches to treat CLD.
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10.
Chronobiological activity of cysteinyl leukotriene receptor 1 during basal and induced autophagy in the ARPE-19 retinal pigment epithelial cell line.
Koller, A, Preishuber-Pflügl, J, Runge, C, Ladek, AM, Brunner, SM, Aigner, L, Reitsamer, H, Trost, A
Aging. 2021;(24):25670-25693
Abstract
Autophagy is an important cellular mechanism for maintaining cellular homeostasis, and its impairment correlates highly with age and age-related diseases. Retinal pigment epithelial (RPE) cells of the eye represent a crucial model for studying autophagy, as RPE functions and integrity are highly dependent on an efficient autophagic process. Cysteinyl leukotriene receptor 1 (CysLTR1) acts in immunoregulation and cellular stress responses and is a potential regulator of basal and adaptive autophagy. As basal autophagy is a dynamic process, the aim of this study was to define the role of CysLTR1 in autophagy regulation in a chronobiologic context using the ARPE-19 human RPE cell line. Effects of CysLTR1 inhibition on basal autophagic activity were analyzed at inactive/low and high lysosomal degradation activity with the antagonists zafirlukast (ZTK) and montelukast (MTK) at a dosage of 100 nM for 3 hours. Abundances of the autophagy markers LC3-II and SQSTM1 and LC3B particles were analyzed in the absence and presence of lysosomal inhibitors using western blot analysis and immunofluorescence microscopy. CysLTR1 antagonization revealed a biphasic effect of CysLTR1 on autophagosome formation and lysosomal degradation that depended on the autophagic activity of cells at treatment initiation. ZTK and MTK affected lysosomal degradation, but only ZTK regulated autophagosome formation. In addition, dexamethasone treatment and serum shock induced autophagy, which was repressed by CysLTR1 antagonization. As a newly identified autophagy modulator, CysLTR1 appears to be a key player in the chronobiological regulation of basal autophagy and adaptive autophagy in RPE cells.