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Autophagy Modulators in Cancer: Focus on Cancer Treatment

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Autophagy Modulators in Cancer: Focus on Cancer Treatment life Review Autophagy Modulators in Cancer: Focus on Cancer Treatment Hye Jin Nam Drug Discovery Platform Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea; [email protected]; Tel.: +82-42-860-7456 Abstract: Uncontrolled autophagy has been associated with the development and progression of various cancers that are resistant to cancer therapy. Therefore, many efforts to modulate uncontrolled autophagy as a cancer treatment have been attempted, from basic science to clinical trials. However, it remains difficult to equally apply autophagy modulators to cancer therapy because autophagy is a double-edged sword in cancer: it can be tumor-suppressive or tumor-protective. Therefore, the precise mechanisms of autophagy modulators and their varied responsiveness to each cancer type should be addressed in detail. This study will describe the precise mechanisms of developing various autophagy modulators, their current therapeutic applications and future perspectives. Keywords: autophagy; autophagy enhancer; autophagy inhibitor; cancer treatment 1. Introduction Autophagy (self-eating) is defined as a homeostatic process that enables the lysoso- mal degradation of unnecessary or dysfunctional organelles or proteins [1]. There are three types of autophagy: microautophagy, chaperone-mediated autophagy (CMA) and Citation: Nam, H.J. Autophagy macroautophagy [2]. Microautophagy is involved with the direct uptake of cargo by the Modulators in Cancer: Focus on lysosome, and little is known about its mechanism [3]. CMA is a selective process and Cancer Treatment. Life 2021, 11, 839. involves substrates with specific motifs (KFERQ or similar KFERQ generated by modi- https://doi.org/10.3390/ fication). Heat-shock cognate chaperone of 70 kDa (Hsc70) recognizes the KFERQ motif life11080839 of the substrate and binds and moves together to the lysosomal membrane. Chaperone selectively binds to LAMP2A on the lysosomal membrane and internalizes the substrate Academic Editors: Evangelos Koustas into the lysosome through LAMP2A. Thus, CMA has not only selective substrates but also and Panagiotis Sarantis specific machinery components [4]. Macroautophagy, usually considered as “autophagy” and thereafter referred to as Received: 28 July 2021 autophagy, is primarily induced by nutrient starvation (e.g., glucose starvation or amino Accepted: 13 August 2021 acid starvation) [5]. Cells deal with starvation by recycling cellular organelles and proteins Published: 17 August 2021 and then generating energy. Autophagy is initiated with the formation of a phagophore, which is also known as an isolation membrane. The membrane source of phagophore has Publisher’s Note: MDPI stays neutral been proposed to originate from the smooth endoplasmic reticulum (ER), mitochondria or with regard to jurisdictional claims in plasma membrane [6]. The conjugation of LC3 to phosphatidylethanolamine (PE) yields published maps and institutional affil- iations. recruitment to the nascent phagophore structure [7]. The precursor proLC3 is cleaved by Atg4 protease into LC3-I with a C-terminal glycine residue, and the C-terminus is then con- jugated to the polar head of PE by Atg complex to form LC3-II. The lipidated LC3 (LC3-II) is localized on the membrane’s inner and outer sides and contributes to the expansion and closure of the phagophore. As LC3-II migrates faster than LC3-I in gel electrophoresis ex- Copyright: © 2021 by the author. periments, it is widely used as a marker for assessing autophagy induction [5]. Phagophore Licensee MDPI, Basel, Switzerland. grows, engulfs cytosolic components and closes to become an autophagosome. Then, This article is an open access article the autophagosome fuses with a lysosome and degrades sequestered contents. Cellular distributed under the terms and conditions of the Creative Commons response to nutrient deprivation is thought to be non-selective autophagy and usually Attribution (CC BY) license (https:// involves random uptake of cytoplasm. Conversely, selective autophagy selectively elimi- creativecommons.org/licenses/by/ nates specific cellular components, such as damaged organelles, or protein aggregates [8]. 4.0/). Moreover, pathogens are targeted for degradation by selective autophagy. Cargo-specific Life 2021, 11, 839. https://doi.org/10.3390/life11080839 https://www.mdpi.com/journal/life Life 2021, 11, x FOR PEER REVIEW 2 of 20 Life 2021, 11, 839 2 of 19 or protein aggregates [8]. Moreover, pathogens are targeted for degradation by selective autophagy. Cargo-specific names have been used to classify the various types of selective autophagynames have (e.g., been usedpexophagy, to classify mitophagy, the various typesaggrephagy, of selective glycophagy, autophagy (e.g., lipophagy pexophagy, ribophagy andmitophagy, xenophagy) aggrephagy, [9,10]. In glycophagy, particular, lipophagy mitophagy ribophagy is strongly and associated xenophagy) with [9, 10tumorigenesis]. In [11,12]particular, (Figure mitophagy 1). is strongly associated with tumorigenesis [11,12] (Figure1). FigureFigure 1. SchematicSchematic diagramdiagram ofof autophagicautophagic progression. progression. There There are are three three types types of of autophagy autophagy in in mam- malianmammalian cells: cells:macroautophagy, macroautophagy, micr microautophagyoautophagy and and chaperone-mediated chaperone-mediated autophagy. autophagy. When When macro- autophagymacroautophagy is induced, is induced, cytoplasmic cytoplasmic materials materials ar aree engulfed engulfed by by double double membranesmembranes (phagophore), (phagophore), closedclosed (autophagosome), fused fused with with the the lysosome lysosome (autolysosome) (autolysosome) and degraded.and degraded. The KFERQ The KFERQ motif motif isis recognized recognized byby Hsc70Hsc70 and and binds binds with with LAMP2A LAMP2A in CMA.in CMA. LAMP2A LAMP2A mediates mediates the translocation the translocation of of thethe substrate substrate intointo lysosomes. lysosomes. Microautophagy Microautophagy directly directly uptakes uptakes the cytoplasmic the cytoplasmic cargo. cargo. Autophagy-modulating drugs have been increasingly used in clinical trials; simul- Autophagy-modulating drugs have been increasingly used in clinical trials; simulta- taneously, many phenotypic screens are being conducted for new drug discovery, which neously,can modulate many autophagy phenotypic for therapeuticscreens are purposes. being conducted However, itfor is notnew easy drug to screendiscovery, and which canidentify modulate new autophagy-modulating autophagy for therapeutic chemicals. purposes. The brief However, analysis of theit is role not of easy autophagy to screen and identifymodulators new through autophagy-modulating LC3-II or autophagosome chemicals. accumulation The briefduring analysis drug of the screening role of may autophagy modulatorsbe misleading. through An increase LC3-II in LC3-IIor autophagosome or autophagosomes accumulation can be interpreted during drug as autophagy screening may beinduction misleading. and blockade: An increase an increase in LC3-II in the or rateauto ofphagosomes autophagosome can formation be interpreted or a decrease as autophagy inductionin the rate and of autophagosome blockade: an increase clearance in following the rate of fusion autophagosome with lysosomes. formation To solve or this a decrease inproblem, the rate autophagic of autophagosome flux probes, suchclearance as GFP-LC3-RFP-LC3 following fusionDG or with mRFP-GFP-tagged lysosomes. To LC3, solve this were developed and used for high-throughput screening to identify autophagy modula- problem, autophagic flux probes, such as GFP-LC3-RFP-LC3ΔG or mRFP-GFP-tagged tors [13,14]. Autophagy flux was quantitatively monitored by calculating the GFP/RFP LC3,ratio were or LC3 developed puncta: the and decreased used for GFP/RFP high-throughput ratio is detected screening by the to autophagyidentify autophagy inducer, mod- ulatorswhereas [13,14]. the autophagy Autophagy inhibitor flux detects was quantitati the increasedvely GFP/RFP monitored ratio. by However,calculating an the assay GFP/RFP ratiousing or an LC3 autophagic puncta: flux the probedecreased has a GFP/RFP limitation, ra astio it doesis detected not distinguish by the autophagy whether the inducer, whereasautophagy the modulators autophagy inhibit inhibitor the initiation detects the step in orcreased lysosomal GFP/RFP fusion stepratio. [15 However,]. To apply an assay usingautophagy an autophagic modulators flux as therapeutics, probe has a more limitation, research as beyond it does screening not distinguish is required whether to the autophagydetermine which modulators steps of inhibit autophagy the areinitiation regulated step by or these lysosomal chemicals. fusion Through step various[15]. To apply autophagyautophagy screeningmodulators methods, as therapeutics, researchers more are discovering research beyond novel autophagy screening modulators is required to de- and/or adding new functions as autophagy modulators to existing drugs [15]. termine which steps of autophagy are regulated by these chemicals. Through various au- tophagy2. Autophagy: screening Tumor methods, Suppressor researchers or Promoter? are discovering novel autophagy modulators and/orIn normaladding cells, new autophagy functions contributesas autopha togy the modulators maintenance to of existing homeostasis. drugs Autophagy [15]. is a mechanism to deal with starvation, but it also plays an essential role in removing substances
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