Begell House Inc.
Critical Reviews™ in Oncogenesis
CRO
0893-9675
23
5-6
2018
Preface: Autophagy and Oncogenesis
v-vi
10.1615/CritRevOncog.v23.i5-6.10
Benjamin
Bonavida
Department of Microbiology, Immunology, &
Molecular Genetics, David Geffen School of Medicine at UCLA, Johnson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90025-1747, USA
Autophagy and Hallmarks of Cancer
247-267
10.1615/CritRevOncog.2018027913
Tianzhi
Huang
Ken & Ruth Davee Department of Neurology, Lou & Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL
Xiao
Song
Ken & Ruth Davee Department of Neurology, Lou & Jean Malnati Brain Tumor Institute, Robert H. Lurie
Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL
Yongyong
Yang
Ken & Ruth Davee Department of Neurology, Lou & Jean Malnati Brain Tumor Institute, Robert H. Lurie
Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL
Xuechao
Wan
Ken & Ruth Davee Department of Neurology, Lou & Jean Malnati Brain Tumor Institute, Robert H. Lurie
Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL
Angel A.
Alvarez
Ken & Ruth Davee Department of Neurology, Lou & Jean Malnati Brain Tumor Institute, Robert H. Lurie
Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL
Namratha
Sastry
Ken & Ruth Davee Department of Neurology, Lou & Jean Malnati Brain Tumor Institute, Robert H. Lurie
Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL
Haizhong
Feng
State Key
Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital,
School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Bo
Hu
Ken & Ruth Davee Department of Neurology, Lou & Jean Malnati Brain Tumor Institute, Robert H. Lurie
Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL
Shi-Yuan
Cheng
Ken & Ruth Davee Department of Neurology, Lou & Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL
therapy
autophagosomes
ATGs
cancer
macroautophagy
Autophagy is a catabolic program that is responsible for the degradation of dysfunctional or unnecessary proteins and organelles to maintain cellular homeostasis. Mechanistically, it involves the formation of double-membrane autophagosomes that sequester cytoplasmic material and deliver it to lysosomes for degradation. Eventually, the material is recycled back to the cytoplasm. Abnormalities of autophagy often lead to human diseases, such as neurodegeneration and cancer. In the case of cancer, increasing evidence has revealed the paradoxical roles of autophagy in both tumor inhibition and tumor promotion. Here, we summarize the context-dependent role of autophagy and its complicated molecular mechanisms in the hallmarks of cancer. Moreover, we discuss how therapeutics targeting autophagy can counter malignant transformation and tumor progression. Overall, the findings of studies discussed here shed new light on exploiting the complicated mechanisms of the autophagic machinery and relevant small-molecule modulators as potential antitumor agents to improve therapeutic outcomes.
Mechanism and Regulation of Autophagy in Cancer
269-280
10.1615/CritRevOncog.2018028394
Uma
Maheswari
DBT-IPLS Programme, Department of Biochemistry and Molecular Biology, Pondicherry University, Pondicherry, India
Sudha Rani
Sadras
DBT-IPLS Programme, Department of Biochemistry and Molecular Biology, Pondicherry University, Pondicherry, India
autophagy
Beclin 1
genome instability
tumor suppression
tumor promotion
Autophagy, or self-eating, is a catabolic process that plays a crucial role in cellular homeostasis by carrying
out bulk degradation of defective or superfluous proteins as well as worn-out organelles through a specialized
structure, the autophagosome, which in turn fuses with the lysosome. Autophagy also alleviates cellular stress induced
by nutrient deprivation, metabolic disturbance, hypoxia, and the like, by recycling intracellular constituents. This role
of autophagy, to provide metabolic precursors especially upon starvation, might also contribute to the survival of cancer cells. The role of autophagy in cancer cells is ambiguous given that its downregulation or upregulation has been observed to depend on cancer stage and pathological grade. Autophagy has been found to exhibit a dual effect on tumorigenesis where it functions to suppress tumor progression by eliminating factors that cause genome instability while promoting survival of cancer cells under unfavorable conditions like therapeutic stress. This review aims to explain the mechanism, regulation, and the dual role of autophagy in cancer.
A New Linkage between the Tumor Suppressor RKIP and Autophagy: Targeted Therapeutics
281-305
10.1615/CritRevOncog.2018027211
Yuhao
Wang
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA
90025-1747
Benjamin
Bonavida
Department of Microbiology, Immunology, &
Molecular Genetics, David Geffen School of Medicine at UCLA, Johnson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90025-1747, USA
Autophagy
LC3
metastasis
NF-kB
resistance
RKIP
survival
survival pathways
therapy
The complexities of molecular signaling in cancer cells have been hypothesized to mediate cross-network
alterations of oncogenic processes such as uncontrolled cell growth, proliferation, acquisition of epithelial-to-mesenchymal transition (EMT) markers, and resistance to cytotoxic therapies. The two biochemically exclusive processes/proteins examined in the present review are the metastasis suppressor Raf-1 kinase inhibitory protein (RKIP) and the cell-intrinsic system of macroautophagy (hereafter referred to as autophagy). RKIP is poorly expressed in human cancer tissues, and low expression levels are correlated with high incidence of tumor growth, metastasis, poor treatment efficacy, and poor prognoses in cancer patients. By comparison, autophagy is a conserved cytoprotective degradation pathway that has been shown to influence the acquisition of resistance to hypoxia and nutrient depletion as well as the regulation of chemo-immuno-resistance and apoptotic evasion. Evidently, a broad library of cancer-relevant studies exists for RKIP and autophagy, although reports of the interactions between pathways involving RKIP and autophagy have been relatively sparse. To circumvent this limitation, the coordinate regulatory and effector mechanisms were examined for both RKIP and autophagy. Here, we propose three putative pathways that demonstrate the inherent pleiotropism and relevance of RKIP and the microtubule-associated protein 1 light chain 3 (MAP1LC3, LC3) on cell growth, proliferation, senescence, and EMT, among the hallmarks of cancer. Our findings suggest that signaling modules involving p53, signal transducer and activator of transcription 3 (STAT3), nuclear factor-κB (NF-κB), and Snail highlight the novel roles for RKIP in the
control of autophagy and vice versa. The suggested potential crosstalk mechanisms are new areas of research in which
to further study RKIP and autophagy in cancer models. These should lead to novel prognostic motifs and will provide
alternative therapeutic strategies for the treatment of unresponsive aggressive cancer types.
Linking Autophagy and the Dysregulated NFκB/ SNAIL/YY1/RKIP/PTEN Loop in Cancer: Therapeutic Implications
307-320
10.1615/CritRevOncog.2018027212
Benjamin
Bonavida
Department of Microbiology, Immunology, &
Molecular Genetics, David Geffen School of Medicine at UCLA, Johnson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90025-1747, USA
Autophagy
NFkB
PTEN
RKIP
SNAIL
therapy
YY1
The role of autophagy in the pathogenesis of various cancers has been well documented in many reports. Autophagy in cancer cells regulates cell proliferation, viability, invasion, epithelial-to-mesenchymal transition (EMT),
metastasis, and responses to chemotherapeutic and immunotherapeutic treatment strategies. These manifestations are the result of various regulatory gene products that govern autophagic, biochemical, and molecular mechanisms. In several human cancer cell models, the presence of a dysregulated circuit—namely, NFκB/SNAIL/YY1/RKIP/PTEN—that plays a major role in the regulation of tumor cell unique characteristics just listed for autophagy-regulated activities. Accordingly, the autophagic mechanism and the dysregulated circuit in cancer cells share many of the same properties and activities. Thus, it has been hypothesized that there must exist a biochemical/molecular link between the two. The present review describes the link and the association of each gene product of the dysregulated circuit with the autophagic mechanism and delineates the presence of crosstalk. Crosstalk between autophagy and the dysregulated circuit is significant and has important implications in the development of targeted therapies aimed at either autophagy or the dysregulated gene products in cancer cells.
Driving Cytotoxic Natural Killer Cells into Melanoma: If CCL5 Plays the Music, Autophagy Calls the Shots
321-332
10.1615/CritRevOncog.2018027526
Malina
Xiao
Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg City, Luxembourg
Muhammad Zaeem
Noman
Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg City, Luxembourg
Ludovic
Menard
Laboratory of Experimental Cancer Research, Department of Oncology; Immuno-Pharmacology and Interactomics, Department of Infection and Immunity, Luxembourg Institute of Health, L-1526 Luxembourg City, Luxembourg
Andy
Chevigne
Immuno-Pharmacology and Interactomics,
Department of Infection and Immunity, Luxembourg Institute of Health, L-1526 Luxembourg City, Luxembourg
Martyna
Szpakowska
Immuno-Pharmacology and Interactomics,
Department of Infection and Immunity, Luxembourg Institute of Health, L-1526 Luxembourg City, Luxembourg
Manon
Bosseler
Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg City, Luxembourg
Markus
Ollert
Immuno-Pharmacology and Interactomics,
Department of Infection and Immunity, Luxembourg Institute of Health, L-1526 Luxembourg City, Luxembourg
Guy
Berchem
Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg City, Luxembourg; Department of Hemato-Oncology, Centre Hospitalier de Luxembourg, L-1210 Luxembourg City, Luxembourg
Bassam
Janji
Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health, L-1526 Luxembourg City, Luxembourg
autophagy
antitumor immunity
natural killer cells
immunotherapies
hypoxia
tumor microenvironment
cytokines
chemokines
Autophagy is a quality control process executed at the basal level in almost all cell types. However, in cancer cells, autophagy is activated by several stimuli, including hypoxia. Depending on tumor type, stage, and genetic
context, autophagy is a double-edged sword. Autophagy promotes regression in newly established tumors; however, it
supports tumor progression in well-established tumors by maintaining cancer cell survival under stress conditions. These data, in addition to the emerging role of autophagy in impairing antitumor immunity, have attracted significant interest in developing autophagy inhibitors as a new approach to cancer treatment. The enthusiasm for developing selective drugs inhibiting autophagy has been seriously challenged by the discovery that most autophagy-related proteins display nonautophagic functions. Autophagy inhibitors chloroquine and hydroxychloroquine are currently being investigated in several clinical trials in combination with standard anticancer therapies. Here, we provide a brief overview on the nonautophagic function of autophagy-related proteins and summarize the major mechanisms whereby autophagy modulation could positively or negatively impact cancer therapies. We also focus on the emerging role of targeting autophagy in the improvement of NK-mediated antitumor immunity through the regulation of CCL5 and its receptors' expression in melanoma, and we provide some clues revealing how autophagy modulators could be exploited to improve cancer immunotherapies.
Herbal Medicine in the Mitigation of Reactive Oxygen Species, Autophagy, and Cancer: A Review
333-346
10.1615/CritRevOncog.2018027408
Anna
Marzvanyan
AT Still University School of Osteopathic Medicine, Mesa, AZ
Vicky
Chen
Columbia University School of Nursing, New York, NY
Boshi
Zhang
Division of Growth and Development, Section of Orthodontics, UCLA School of Dentistry, Los Angeles, CA
Greg
Asatrian
Division of Growth and Development, Section of Orthodontics, UCLA School of Dentistry, Los Angeles, CA
herbal medicine
reactive oxygen species
autophagy
apoptosis
Since the discovery of autophagy in the mid-2000s, the interest in autophagy-related processes within the
scientific community has been burgeoning. Countless authors have investigated its function in cellular homeostasis, but
arguably of higher importance is its role during pathology. Although primarily a catabolic process, in cancer cells autophagy has numerous downstream effects, being observed to be both pro- and anti-apoptotic. One of the primary factors
mediating this differential role of autophagy is the accumulation or sequestration of reactive oxygen species (ROS). Until recently, despite its increasing popularity in the Western world, the efficacy of herbal supplements has been largely anecdotal. Herein, we reviewed the ten most commonly studied herbs in cancer research and their impact on ROS regulation, on the activation and inhibition of autophagy, and ultimately on cancer cell death.
Molecular Responses of Cancers by Natural Products: Modifications of Autophagy Revealed by Literature Analysis
347-370
10.1615/CritRevOncog.2018027566
Andy Wai Kan
Yeung
Oral and Maxillofacial Radiology, Applied Oral Sciences, Faculty of Dentistry, University of Hong Kong, Hong
Kong, China
Amr
El-Demerdash
Sorbonne Universités, Centre National de la Recherche Scientifique, Muséum National d'Histoire Naturelle, Molécules de Communication et Adaptation des Micro-Organismes, UMR 7245 CNRS/MNHN, France;
Organic Chemistry Division, Chemistry Department, Faculty of Science, Mansoura University, Mansoura-35516, Egypt
Ioana
Berindan-Neagoe
MEDFUTURE Research Center for Advanced Medicine, 400012 Cluj-Napoca, Romania; Research Center
for Functional Genomics, Biomedicine, and Translational Medicine, Institute of Doctoral Studies, "Iuliu Hatieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; Department of Experimental Pathology, "Prof. Ion Chiricuta", The Oncology Institute, Cluj-Napoca, Romania
Atanas G.
Atanasov
Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Magdalenka, Poland; Department of Pharmacognosy, University of Vienna, Vienna, Austria
Yuh-Shan
Ho
Trend Research Centre, Asia University, Wufeng, Taichung County 41354, Taiwan
autophagy
bibliometric
cancer
citation analysis
natural product
jasplakinolide
phytochemical
Although numerous bibliometric studies have examined various aspects of cancer research, the landscape of scientific studies focusing on natural products in cancer research has not been characterized. Using the Web of Science Core Collection online database, we identify and analyze scientific articles on natural products in cancer-related research. English is the language of publication for 99% of articles. In general, annual citation count of an article increases quickly after publication, reaches a plateau in the second year, stays in this plateau for 10 yr, and then begins to fall. The five most contributing journal categories are medicinal chemistry, contributing the most at 1890 articles (24% of 8012 articles); oncology (20%, with 1572 articles); pharmacology and pharmacy (19%, with 1557); biochemistry and molecular biology (15%, with 1225); and plant sciences (11%, with 883 articles). The United States and Spain yield a larger number of articles with high average citations, and China has been increasing since 2009. Apoptosis and cytotoxicity are the two most-frequently used keywords. Effects of natural products on autophagy with a relevance to cancer are mentioned in 69 publications. Our literature analysis reveals a dynamically evolving landscape and an increasing volume of research investigations
that are focused on the study of natural products in the context of cancer. Curcumin, flavonoids, and resveratrol
are the most-frequently mentioned natural products. Cancer of the breast, prostate, and colon are the most-frequently
mentioned cancers.
Index, Volume 23, 2018
371-374
10.1615/CritRevOncog.v23.i5-6.90