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Download references. NIH CA, CA and CA AT. We thank Christina Towers, PhD, for her assistance with the development of Fig. Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, , USA. Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, , USA.
You can also search for this author in PubMed Google Scholar. Correspondence to Andrew Thorburn. Reprints and permissions. Mulcahy Levy, J. Autophagy in cancer: moving from understanding mechanism to improving therapy responses in patients.
Cell Death Differ 27 , — Download citation. Received : 04 September Revised : 12 November Accepted : 18 November Published : 13 December Issue Date : March Anyone you share the following link with will be able to read this content:.
Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content Thank you for visiting nature. Download PDF. Subjects Cancer. Abstract Autophagy allows for cellular material to be delivered to lysosomes for degradation resulting in basal or stress-induced turnover of cell components that provide energy and macromolecular precursors.
You have full access to this article via your institution. Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma Article Open access 29 January Targeted activation of ferroptosis in colorectal cancer via LGR4 targeting overcomes acquired drug resistance Article 30 January Lipids as mediators of cancer progression and metastasis Article 25 January Facts Autophagy has complicated and often competing roles in cancer.
Open Questions How should we target autophagy to maximize benefit—early vs. Introduction In , Yoshinori Ohsumi was awarded the Nobel Prize for Physiology or Medicine for his work on autophagy and its impact in the study of human health and disease [ 1 ].
Autophagy as a therapeutically targetable process Macroautophagy referred to hereafter as autophagy is a highly conserved catabolic process with the formation of double membrane vesicles called autophagosomes that engulf cellular proteins and organelles for delivery to the lysosome [ 17 , 18 ] Fig.
Full size image. Table 1 Pre-clinical and clinical inhibitors of autophagy. Full size table. Table 2 Human clinical autophagy inhibition trials. References Assembly TN. Article CAS PubMed PubMed Central Google Scholar Rao S, Tortola L, Perlot T, Wirnsberger G, Novatchkova M, Nitsch R, et al.
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Article CAS PubMed PubMed Central Google Scholar Wolpin BM, Rubinson DA, Wang X, Chan JA, Cleary JM, Enzinger PC, et al. In this short review, we will mainly address the role of autophagy and its different functional forms in cancer, and its implication in cancer therapy.
Nevertheless, it is important to mention that recent studies have shown that CMA may be also important for tumor growth, progression and therapy and that pharmacological approaches that inhibit macroautophagy may also affect CMA [8,9].
Cancer was one of the first diseases to be associated to autophagy []. Nevertheless, the exact molecular mechanisms and the role of autophagy in cancer cells is not yet clearly defined, being even paradoxical. While at early stages, autophagy usually acts as a tumor suppressor allowing cells to discard damaged cellular contents, decreasing ROS and DNA damage, in more advanced stages of tumor development, it may help cancer cells to survive under low-oxygen and low-nutrient conditions, acting as a tumor promoter [3,15].
Actually, the dependence of tumor cells on autophagy is highly variable. While some tumor models like pancreatic cancer display increased autophagy levels in basal situations including in plenty nutrient conditions , with autophagy having a role in the maintenance of tumor growth [16], results from other studies, comparing the levels of autophagy in tumor cells with their corresponding non-tumor cells, show disparate data between different tumor models for a thorough review please see [17].
Importantly, autophagy plays also a role in cancer response to therapy since cancer therapies mostly inflict stress and damage to cells to induce cell death [18]. Indeed, several studies showed that increased autophagy leads to resistance to both chemo- and radiotherapy, while several others show that many anticancer drugs induce autophagy-related cell death in cancer cells [22,23].
The fact that many of the currently used clinically approved anticancer strategies have been described as inducing autophagy, makes the understanding of the functional role of autophagy within a specific cancer context much more relevant, as it could provide new means for the enhancement of antitumor drugs and radiation effectiveness.
Although, traditionally, autophagy has been seen as a pro-survival cytoprotective mechanism, different studies have shown that it may result in other outcomes. Currently, at least four distinct functional forms of autophagy have been described [24,25]: i Cytoprotective, when cells die or arrest if autophagy is inhibited; ii Cytotoxic, when autophagy induction results in cell death and its blockage results in cell survival; iii Cytostatic, when autophagy induction results in cell growth arrest and iv Nonprotective, if autophagy does not affect cell growth once blocked.
These forms are distinguished on only based on their functional characteristics, having similar morphologic, biochemical or molecular profiles [24].
As already referred, the different functional forms of autophagy affect the cellular response to anticancer therapies. Targeting cytoprotective autophagy has been at the basis for multiple clinical trials.
Indeed, if increased autophagy confers tumor resistance to death-inducing agents, its inhibition will allow an enhanced response to treatment [26].
There are several autophagy inhibitors already identified and that have been classified as: early-stage inhibitors, if blocking autophagosome formation [such as 3-Methyladenine 3-MA , wortmannin, and LY] orlate-stage inhibitors, acting at the level of the autophagosome-lysosome fusion and degradation steps [such as chloroquine CQ , hydroxychloroquine HCQ , bafilomycin A1, and monensin].
Studies using, not only these pharmacological autophagy inhibitors, but also genetic silencing or knockdown of autophagy-associated genes, resulted in increased tumor cell sensitivity to the autophagy-inducing stimulus, usually via the promotion of apoptosis [24,26].
Several clinical trials have been evaluating the use of autophagy inhibitors particularly HCQ in combination to chemo- and radiotherapy to improve its efficacy [27,28].
A study carried out in melanoma patients using HCQ in combination with the mTOR inhibitor temsirolimus showed an improvement of the median progression-free survival to 3. More recently, the use of HCQ in combination with gemcitabine in pancreatic ductal adenocarcinoma patients caused significant decreases in the disease biomarker, CA 19—9, with the mean overall survival being extended to nearly 3 years [28,31].
Moreover, these type of compounds, although being already FDA approved, have to be administered in higher concentrations to inhibit autophagy and are retained for long periods of time in patients some studies showing patients retaining HCQ in their system up to 5 years [28,32]. On the other hand, autophagy induction may help improve the effect of anticancer therapies when autophagy is cytotoxic, by inducing cell death by itself or by the activation of other cell death mechanism, namely apoptosis [33,34].
For example, the combination of Vitamin D with radiation promoted cytotoxic autophagy in breast tumor cells [35,36]. Resveratrol and curcumin caused cell death in several human tumor cell lines through apoptosis and autophagy [37,38].
Naphthazarin, a naphthoquinone compound acting as microtubule depolymerizing agent was shown to induce cell death in lung cancer cells through apoptosis and autophagy [39].
In addition, the small molecule STF induced autophagic cell death in Von Hippel Lindau VHL -deficient renal cell carcinoma cells [40] and TXA1, a thioxantonic small molecule, decreased the viability of melanoma and breast cancer cells through the induction of autophagy [41].
The role of immune response has been gaining particular interest for cancer therapy. Recently, autophagy has also been described as playing an important role in the regulation of immune recognition and response [42].
It has been demonstrated that autophagy increases tumor cells immunogenicity, being involved in tumor antigen processing and in the subsequent activation of the effector T cells. Thus, strategies aiming at autophagy induction could serve as adjuvant to stimulate the antitumor immune response.
For example, the use of tumor autophagosome-derived vaccines have been found to induce cytotoxic immune cells and, consequently, antitumor activity in mice bearing lung carcinoma and melanoma cell lines [43]. Recent studies show that, since increased levels of autophagy in cancer cell suppresses the antitumor immune response, autophagy inhibition improves antitumor immune response in immunotherapeutic strategies, such as adoptive transfer of T cells, vaccines, administration of antibodies or recombinant cytokines [44] Based on published findings, autophagy inhibition may increase the cytotoxicity of effector T and NK cells once they have been activated to lyse the tumor cells.
The combination of high doses of IL-2 with chloroquine increased long term survival, decreased vascular leakage associated toxicity, and enhanced immune cell proliferation and infiltration in the liver and spleen [45]. Autophagy plays also a fundamental role in increasing the immunogenicity of the tumor cell, participates in the antigen processing and in the subsequent activation of the effector T cells, and its induction could be exploited as adjuvant strategy to stimulate the antitumor immune response [43,46].
The understanding under which circumstances inducers or inhibitors of autophagy affect the therapeutic efficacy of anticancer treatments will be important to improve the rational use of such modulators, since the data available do not yet allow us to realize this [46].
Autophagy plays an important role as a stress response mechanism to chemotherapeutic drugs and radiation in cancer cells. There are at least four functional forms of autophagy that may occur in response to chemotherapy or radiation: cytoprotective, nonprotective, cytotoxic and cytotastic.
Currently, is not possible to predict which form will be induced by a particular therapy, since these forms of autophagy have no clear-cut morphologic, biochemical, or molecular distinctions.
In some circumstances, autophagy protects tumor cells from cancer therapy while, in others it is associated with cancer cell killing. Modulation of autophagy may represent an important therapeutic opportunity to enhance the efficacy of anticancer therapies.
The future challenge for autophagy research in cancer therapy is to find ways to identify which functional form of autophagy is activated, in specific tumor models, and which tumors may be most effectively treated by autophagy modulation.
A better understanding of the role of autophagy in different tumor models will provide new therapeutic tools for more effective cancer therapeutic strategies. Received date: January 24, Accepted date: February 16, Published date: February 18, This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Grácio D, Magro F, Lima RT, Máximo V An overview on the role of autophagy in cancer therapy. Hematol Med Oncol 2: DOI: Cancer Signaling and Metabolism research group, Instituto de Patologia e Imunologia Molecular da Universidade do Porto IPATIMUP , Porto, Portugal.
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Links Advanced knowledge sharing through global community… Read More. Take a look at the Recent articles. An overview on the role of autophagy in cancer therapy Daniela Grácio. Departmento de Biomedicina, Faculdade de Medicina da Universidade do Porto, Porto, Portugal Contributed equally to this work, and should be considered joint first authors E-mail : bhuvaneswari.
Departmento de Biomedicina, Faculdade de Medicina da Universidade do Porto, Porto, Portugal Contributed equally to this work, and should be considered joint first authors.
Instituto de Investigação e Inovação em Saúde i3S , Universidade do Porto, Porto, Portugal Instituto de Patologia e Imunologia Molecular da Universidade do Porto IPATIMUP , Porto, Portugal Departmento de Patologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal.
Introduction Autophagy self-eating is a highly conserved catabolic process with critical functions in the maintenance of cellular homeostasis under normal growth conditions and in the preservation of cell viability under stress [1].
Those proteins contain a specific amino acid motif KFERQ, or biochemically related , which is recognized by the HSP, and once unfolded, they are translocated directly into the lysosome, via the lysosome-associated membrane protein 2A LAMP2A [4,5] Several studies have already demonstrated that autophagy plays more roles than the initially expected, including: cellular adaptation to starvation, intracellular protein and organelle clearance, development, anti-aging, elimination of microorganisms, cell death and antigen presentation [6].
Autophagy in cancer Cancer was one of the first diseases to be associated to autophagy []. Functional forms of autophagy and their implications for cancer therapy Although, traditionally, autophagy has been seen as a pro-survival cytoprotective mechanism, different studies have shown that it may result in other outcomes.
Autophagy modulation as a therapeutic strategy to improve anticancer strategies As already referred, the different functional forms of autophagy affect the cellular response to anticancer therapies.
Autophagy in immunotherapy The role of immune response has been gaining particular interest for cancer therapy. Autophagy plays also a fundamental role in increasing the immunogenicity of the tumor cell, participates in the antigen processing and in the subsequent activation of the effector T cells, and its induction could be exploited as adjuvant strategy to stimulate the antitumor immune response [43,46] The understanding under which circumstances inducers or inhibitors of autophagy affect the therapeutic efficacy of anticancer treatments will be important to improve the rational use of such modulators, since the data available do not yet allow us to realize this [46].
Summary Autophagy plays an important role as a stress response mechanism to chemotherapeutic drugs and radiation in cancer cells. References Mizushima N Autophagy: process and function. Genes Dev Mol Pharmacol
Canceg cutting-edge scholarly communications to Autophagy and cancer, anc them to utilize Autophagy and cancer Forskolin and herbal medicine effectively. We aim znd bring about a change in modern scholarly communications through the effective use of editorial and publishing polices. Advanced knowledge sharing through global community…. Daniela Grácio. Departmento de Biomedicina, Faculdade de Medicina da Universidade do Porto, Porto, Portugal. Melanie M. HippertCabcer Muscle cramp relief. O'Toole Canfer, Andrew Thorburn; Autophagy in Cancer: Good, Bad, or Both?. Cancer Res 1 October Energy-boosting testosterone boosters 66 19 : — Autophagy has been recognized as an important cellular process for at least 50 years; however, it is only with the recent identification of key regulators of autophagy Atg genes that we have begun a mechanistic exploration of its importance in cancer.
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