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Autophagy and Human Cancers
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Autophagy and Human Cancers

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Autophagy".

Deadline for manuscript submissions: closed (25 September 2023) | Viewed by 17563

Special Issue Editors

Dr. Maria Condello

E-Mail Website
Guest Editor
National Center for Drug Research and Evaluation, National Institute of Health, Viale Regina Elena, 00161 Rome, Italy
Interests: characterization of multidrug-resistant tumor cells; in vitro study of apoptosis induced by chemotherapeutic drugs; in vitro study of autophagy (cell survival mechanism or type II programmed cell death); in vitro study of new anticancer strategies based on the use of natural products in combination with drugs, on electrochemotherapy, and on liposomes; study of interaction between cells and metal nanoparticles (ZnO or Ag-NPs) to investigate nanotoxicology
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Stefania Meschini

E-Mail Website
Co-Guest Editor
National Center for Drug Research and Evaluation, National Institute of Health, Viale Regina Elena, 00161 Rome, Italy
Interests: ultrastructural pathology; nanomedicine; nanotoxicology; cell biology; anticancer therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Autophagy is a conserved catabolic process, essential for the maintenance of cellular homeostasis. In cancer, autophagy is related to the cell type, the different tumor, the microenvironment and the stage of the disease. During tumor development, autophagy is able to disfavor malignant transformation, limiting the production of reactive oxygen species and DNA damage. In advanced stages of the disease, autophagy evolves to support cancer progression through the regulation of the immune response or the secretion of cytokines and growth factors. Furthermore, autophagy can be involved in mechanisms of resistance to anticancer therapy. In this Special Issue, we will try to improve the understanding of autophagy mechanisms, especially those involved in the growth and aggressiveness of the tumor and the regulation of resistance to chemotherapy.

Dr. Maria Condello
Prof. Dr. Stefania Meschini
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • autophagy
  • cell death
  • cancer
  • resistance mechanisms
  • microenvironment

Published Papers (7 papers)

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Research

Jump to: Review

16 pages, 4028 KiB  
Article
Curcumin-Mediated Resistance to Lenvatinib via EGFR Signaling Pathway in Hepatocellular Carcinoma
by Katsuki Miyazaki, Yuji Morine, Caiming Xu, Chiharu Nakasu, Yuma Wada, Hiroki Teraoku, Shinichiro Yamada, Yu Saito, Tetsuya Ikemoto, Mitsuo Shimada and Ajay Goel
Cells 2023, 12(4), 612; https://doi.org/10.3390/cells12040612 - 14 Feb 2023
Cited by 4 | Viewed by 3529
Abstract
Lenvatinib is a multi-kinase inhibitor approved as a first-line treatment for patients with unresectable advanced hepatocellular carcinoma (HCC). However, its response rate is unsatisfactory, primarily due to the acquisition of resistance, which limits its clinical significance for treating patients with HCC. Recent evidence [...] Read more.
Lenvatinib is a multi-kinase inhibitor approved as a first-line treatment for patients with unresectable advanced hepatocellular carcinoma (HCC). However, its response rate is unsatisfactory, primarily due to the acquisition of resistance, which limits its clinical significance for treating patients with HCC. Recent evidence suggests that epidermal growth factor receptor (EGFR) activation can trigger Lenvatinib-resistance; and is considered an important therapeutic target in HCC. Curcumin, one of the most studied naturally occurring botanicals with robust anti-cancer activity, is also reported to be a potent tyrosine kinase inhibitor. In this study, we hypothesized that the anti-EGFR potential of Curcumin might help overcome Lenvatinib resistance in HCC. We established two Lenvatinib-resistant cells and discovered that a combination of Curcumin and Lenvatinib exhibited a synergistic anti-tumor efficacy in the resistant HCC cell lines. In line with previous reports, Lenvatinib-resistant cell lines revealed significant activation of the EGFR, and genomewide transcriptomic profiling analysis identified that the PI3K-AKT pathway was associated with Lenvatinib resistance. The combination treatment with Curcumin and Lenvatinib dramatically suppressed gene and protein expression of the EGFR-PI3K-AKT pathway, suggesting Curcumin overcomes Lenvatinib resistance via inhibition of EGFR. We further validated these findings in tumor spheroids derived from resistant cell lines. In conclusion, we, for the first time, report that Curcumin reverses Lenvatinib resistance in HCC, and that their combination has clinical application potential for adjunctive treatment in HCC. Full article
(This article belongs to the Special Issue Autophagy and Human Cancers)
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23 pages, 9217 KiB  
Article
Autophagy Activation Associates with Suppression of Prion Protein and Improved Mitochondrial Status in Glioblastoma Cells
by Paola Lenzi, Carla L. Busceti, Gloria Lazzeri, Rosangela Ferese, Francesca Biagioni, Alessandra Salvetti, Elena Pompili, Valerio De Franchis, Stefano Puglisi-Allegra, Alessandro Frati, Michela Ferrucci and Francesco Fornai
Cells 2023, 12(2), 221; https://doi.org/10.3390/cells12020221 - 04 Jan 2023
Cited by 5 | Viewed by 1585
Abstract
Cells from glioblastoma multiforme (GBM) feature up-regulation of the mechanistic Target of Rapamycin (mTOR), which brings deleterious effects on malignancy and disease course. At the cellular level, up-regulation of mTOR affects a number of downstream pathways and suppresses autophagy, which is relevant for [...] Read more.
Cells from glioblastoma multiforme (GBM) feature up-regulation of the mechanistic Target of Rapamycin (mTOR), which brings deleterious effects on malignancy and disease course. At the cellular level, up-regulation of mTOR affects a number of downstream pathways and suppresses autophagy, which is relevant for the neurobiology of GBM. In fact, autophagy acts on several targets, such as protein clearance and mitochondrial status, which are key in promoting the malignancy GBM. A defective protein clearance extends to cellular prion protein (PrPc). Recent evidence indicates that PrPc promotes stemness and alters mitochondrial turnover. Therefore, the present study measures whether in GBM cells abnormal amount of PrPc and mitochondrial alterations are concomitant in baseline conditions and whether they are reverted by mTOR inhibition. Proteins related to mitochondrial turnover were concomitantly assessed. High amounts of PrPc and altered mitochondria were both mitigated dose-dependently by the mTOR inhibitor rapamycin, which produced a persistent activation of the autophagy flux and shifted proliferating cells from S to G1 cell cycle phase. Similarly, mTOR suppression produces a long-lasting increase of proteins promoting mitochondrial turnover, including Pink1/Parkin. These findings provide novel evidence about the role of autophagy in the neurobiology of GBM. Full article
(This article belongs to the Special Issue Autophagy and Human Cancers)
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15 pages, 3676 KiB  
Article
Robustness of the Autophagy Pathway to Somatic Copy Number Losses
by Pierfrancesco Polo, Niklas Gremke, Thorsten Stiewe and Michael Wanzel
Cells 2022, 11(11), 1762; https://doi.org/10.3390/cells11111762 - 27 May 2022
Viewed by 1746
Abstract
Autophagy allows cells to temporarily tolerate energy stress by replenishing critical metabolites through self-digestion, thereby attenuating the cytotoxic effects of anticancer drugs that target tumor metabolism. Autophagy defects could therefore mark a metabolically vulnerable cancer state and open a therapeutic window. While mutations [...] Read more.
Autophagy allows cells to temporarily tolerate energy stress by replenishing critical metabolites through self-digestion, thereby attenuating the cytotoxic effects of anticancer drugs that target tumor metabolism. Autophagy defects could therefore mark a metabolically vulnerable cancer state and open a therapeutic window. While mutations of autophagy genes (ATGs) are notably rare in cancer, haploinsufficiency network analyses across many cancers have shown that the autophagy pathway is frequently hit by somatic copy number losses of ATGs such as MAP1LC3B/ATG8F (LC3), BECN1/ATG6 (Beclin-1), and ATG10. Here, we used CRISPR/Cas9 technology to delete increasing numbers of copies of one or more of these ATGs in non-small cell lung cancer cells and examined the effects on sensitivity to compounds targeting aerobic glycolysis, a hallmark of cancer metabolism. Whereas the complete knockout of one ATG blocked autophagy and led to profound metabolic vulnerability, this was not the case for combinations of different nonhomozygous deletions. In cancer patients, the effect of ATG copy number loss was blunted at the protein level and did not lead to the accumulation of p62 as a sign of reduced autophagic flux. Thus, the autophagy pathway is shown to be markedly robust and resilient, even with the concomitant copy number loss of key autophagy genes. Full article
(This article belongs to the Special Issue Autophagy and Human Cancers)
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Review

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23 pages, 2354 KiB  
Review
Dissecting the Role of Autophagy-Related Proteins in Cancer Metabolism and Plasticity
by Liliana Torres-López and Oxana Dobrovinskaya
Cells 2023, 12(20), 2486; https://doi.org/10.3390/cells12202486 - 19 Oct 2023
Viewed by 1574
Abstract
Modulation of autophagy as an anticancer strategy has been widely studied and evaluated in several cell models. However, little attention has been paid to the metabolic changes that occur in a cancer cell when autophagy is inhibited or induced. In this review, we [...] Read more.
Modulation of autophagy as an anticancer strategy has been widely studied and evaluated in several cell models. However, little attention has been paid to the metabolic changes that occur in a cancer cell when autophagy is inhibited or induced. In this review, we describe how the expression and regulation of various autophagy-related (ATGs) genes and proteins are associated with cancer progression and cancer plasticity. We present a comprehensive review of how deregulation of ATGs affects cancer cell metabolism, where inhibition of autophagy is mainly reflected in the enhancement of the Warburg effect. The importance of metabolic changes, which largely depend on the cancer type and form part of a cancer cell’s escape strategy after autophagy modulation, is emphasized. Consequently, pharmacological strategies based on a dual inhibition of metabolic and autophagy pathways emerged and are reviewed critically here. Full article
(This article belongs to the Special Issue Autophagy and Human Cancers)
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29 pages, 5490 KiB  
Review
Autophagy and Breast Cancer: Connected in Growth, Progression, and Therapy
by Qitong Wu and Dipali Sharma
Cells 2023, 12(8), 1156; https://doi.org/10.3390/cells12081156 - 14 Apr 2023
Cited by 8 | Viewed by 3036
Abstract
Despite an increase in the incidence of breast cancer worldwide, overall prognosis has been consistently improving owing to the development of multiple targeted therapies and novel combination regimens including endocrine therapies, aromatase inhibitors, Her2-targeted therapies, and cdk4/6 inhibitors. Immunotherapy is also being actively [...] Read more.
Despite an increase in the incidence of breast cancer worldwide, overall prognosis has been consistently improving owing to the development of multiple targeted therapies and novel combination regimens including endocrine therapies, aromatase inhibitors, Her2-targeted therapies, and cdk4/6 inhibitors. Immunotherapy is also being actively examined for some breast cancer subtypes. This overall positive outlook is marred by the development of resistance or reduced efficacy of the drug combinations, but the underlying mechanisms are somewhat unclear. It is interesting to note that cancer cells quickly adapt and evade most therapies by activating autophagy, a catabolic process designed to recycle damaged cellular components and provide energy. In this review, we discuss the role of autophagy and autophagy-associated proteins in breast cancer growth, drug sensitivity, tumor dormancy, stemness, and recurrence. We further explore how autophagy intersects and reduces the efficacy of endocrine therapies, targeted therapies, radiotherapy, chemotherapies as well as immunotherapy via modulating various intermediate proteins, miRs, and lncRNAs. Lastly, the potential application of autophagy inhibitors and bioactive molecules to improve the anticancer effects of drugs by circumventing the cytoprotective autophagy is discussed. Full article
(This article belongs to the Special Issue Autophagy and Human Cancers)
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31 pages, 3152 KiB  
Review
Canonical and Noncanonical ER Stress-Mediated Autophagy Is a Bite the Bullet in View of Cancer Therapy
by Rashedul Alam, Mohammad Fazlul Kabir, Hyung-Ryong Kim and Han-Jung Chae
Cells 2022, 11(23), 3773; https://doi.org/10.3390/cells11233773 - 25 Nov 2022
Cited by 2 | Viewed by 2585
Abstract
Cancer cells adapt multiple mechanisms to counter intense stress on their way to growth. Tumor microenvironment stress leads to canonical and noncanonical endoplasmic stress (ER) responses, which mediate autophagy and are engaged during proteotoxic challenges to clear unfolded or misfolded proteins and damaged [...] Read more.
Cancer cells adapt multiple mechanisms to counter intense stress on their way to growth. Tumor microenvironment stress leads to canonical and noncanonical endoplasmic stress (ER) responses, which mediate autophagy and are engaged during proteotoxic challenges to clear unfolded or misfolded proteins and damaged organelles to mitigate stress. In these conditions, autophagy functions as a cytoprotective mechanism in which malignant tumor cells reuse degraded materials to generate energy under adverse growing conditions. However, cellular protection by autophagy is thought to be complicated, contentious, and context-dependent; the stress response to autophagy is suggested to support tumorigenesis and drug resistance, which must be adequately addressed. This review describes significant findings that suggest accelerated autophagy in cancer, a novel obstacle for anticancer therapy, and discusses the UPR components that have been suggested to be untreatable. Thus, addressing the UPR or noncanonical ER stress components is the most effective approach to suppressing cytoprotective autophagy for better and more effective cancer treatment. Full article
(This article belongs to the Special Issue Autophagy and Human Cancers)
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15 pages, 4115 KiB  
Review
Autophagy-Associated Immunogenic Modulation and Its Applications in Cancer Therapy
by Zhuxi Duan, Yu Shi, Qun Lin, Ahmed Hamaï, Maryam Mehrpour and Chang Gong
Cells 2022, 11(15), 2324; https://doi.org/10.3390/cells11152324 - 28 Jul 2022
Cited by 6 | Viewed by 2719
Abstract
Autophagy, a lysosome-mediated cellular degradation pathway, recycles intracellular components to maintain metabolic balance and survival. Autophagy plays an important role in tumor immunotherapy as a “double-edged sword” that can both promote and inhibit tumor progression. Autophagy acts on innate and adaptive immunity and [...] Read more.
Autophagy, a lysosome-mediated cellular degradation pathway, recycles intracellular components to maintain metabolic balance and survival. Autophagy plays an important role in tumor immunotherapy as a “double-edged sword” that can both promote and inhibit tumor progression. Autophagy acts on innate and adaptive immunity and interacts with immune cells to modulate tumor immunotherapy. The discovery of autophagy inducers and autophagy inhibitors also provides new insights for clinical anti-tumor therapy. However, there are also difficulties in the application of autophagy-related regulators, such as low bioavailability and the lack of efficient selectivity. This review focuses on autophagy-related immunogenic regulation and its application in cancer therapy. Full article
(This article belongs to the Special Issue Autophagy and Human Cancers)
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