• Oral squamous cell carcinoma (OSCC)
• epithelial-to-mesenchymal transition (EMT)
• exosome

• Humans
• Exosomes/metabolism
• Epithelial-Mesenchymal Transition/physiology
• Mouth Neoplasms/pathology
• Mouth Neoplasms/immunology
• Mouth Neoplasms/metabolism
• Tumor Microenvironment/immunology
• Carcinoma, Squamous Cell/pathology
• Carcinoma, Squamous Cell/immunology
• Carcinoma, Squamous Cell/metabolism
• Signal Transduction/physiology
• Squamous Cell Carcinoma of Head and Neck/pathology
• Squamous Cell Carcinoma of Head and Neck/immunology
• Squamous Cell Carcinoma of Head and Neck/metabolism

• Autophagy
• Cancer progression
• Epigenetic
• Gastric cancer
• Gastrointestinal cancer
• Long non-coding RNAs

• Stomach Neoplasms/genetics
• Stomach Neoplasms/pathology
• Stomach Neoplasms/therapy
• Humans
• RNA, Long Noncoding/genetics
• RNA, Long Noncoding/metabolism
• Autophagy/genetics
• Gene Expression Regulation, Neoplastic
• Tumor Microenvironment
• Drug Resistance, Neoplasm/genetics
• Epigenesis, Genetic
• Disease Progression
• Prognosis

• cancer stem cell
• combination therapy
• drug resistance
• immunogenicity
• inflammation
• mitophagy

• Humans
• Autophagy
• Neoplasms/metabolism
• Neoplasms/pathology
• Neoplasms/drug therapy
• Inflammasomes/metabolism
• NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
• NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors

• The authors received no specific funding for this work.

• Autophagy
• cancer drug resistance
• immunotherapy
• therapeutic approaches
• tumor microenvironment remodeling

• Humans
• Autophagy/drug effects
• Autophagy/physiology
• Autophagy/immunology
• Neoplasms/drug therapy
• Neoplasms/immunology
• Neoplasms/pathology
• Drug Resistance, Neoplasm/immunology
• Animals
• Antineoplastic Agents/therapeutic use
• Antineoplastic Agents/pharmacology
• Signal Transduction/drug effects
• Tumor Escape/drug effects
• Immune Evasion
• Tumor Microenvironment/immunology
• Tumor Microenvironment/drug effects

• R01 GM053396 NIGMS NIH HHS

• Autophagy
• Cancer
• Long Non-Coding RNA
• Molecular Mechanisms
• NEAT1
• Therapeutic Resistance
• Tumorigenesis

• Humans
• RNA, Long Noncoding/genetics
• RNA, Long Noncoding/metabolism
• Autophagy/physiology
• Neoplasms/pathology
• Neoplasms/metabolism
• Carcinogenesis/metabolism
• Carcinogenesis/genetics
• Drug Resistance, Neoplasm
• Gene Expression Regulation, Neoplastic
• Animals

• Autophagy
• Autophagy inducers
• Autophagy inhibitors
• Nature-derived compounds
• Skin cancer
• Synthetic compounds

• Autophagy
• Epigenetic regulation
• Gastrointestinal cancer
• Non-coding RNAs
• Target therapies

• Humans
• Autophagy/drug effects
• Autophagy/genetics
• Epigenesis, Genetic
• Gastrointestinal Neoplasms/genetics
• Gastrointestinal Neoplasms/pathology
• RNA, Untranslated/genetics
• RNA, Untranslated/metabolism
• Gene Expression Regulation, Neoplastic
• Drug Resistance, Neoplasm/genetics
• Antineoplastic Agents/therapeutic use
• Antineoplastic Agents/pharmacology

• autophagy
• differentiation
• epidermal progenitor cells
• skin
• squamous cell carcinoma

• Animals
• Mice
• Autophagy
• Autophagy-Related Proteins/metabolism
• Autophagy-Related Proteins/genetics
• Carcinogenesis/metabolism
• Carcinogenesis/pathology
• Carcinogenesis/genetics
• Cell Differentiation
• Cell Nucleus/metabolism
• Epidermal Cells/metabolism
• Epidermis/metabolism
• Epidermis/pathology
• Keratinocytes/metabolism
• Keratinocytes/cytology
• Mice, Knockout
• Skin Neoplasms/pathology
• Skin Neoplasms/metabolism
• Skin Neoplasms/genetics
• Vesicle-Associated Membrane Protein 2/metabolism
• Vesicle-Associated Membrane Protein 2/genetics

• P30 ES030283 NIEHS NIH HHS
• T32 GM144292 NIGMS NIH HHS
• R01 OD023700 NIH HHS
• R01 DA047785 NIDA NIH HHS
• R01 AR078555 NIAMS NIH HHS
• R21 AR080761 NIAMS NIH HHS

• Acute leukemia
• Arsenic resistance protein 2
• Cell proliferation
• Minnelide
• Triptolide
• miR-190a-3p

• Phenanthrenes/pharmacology
• Animals
• Humans
• Diterpenes/pharmacology
• MicroRNAs
• Epoxy Compounds/pharmacology
• Cell Line, Tumor
• Mice
• Apoptosis/drug effects
• Xenograft Model Antitumor Assays
• Leukemia/drug therapy
• Organophosphates/pharmacology
• Antineoplastic Agents, Phytogenic/pharmacology

• AMPK
• Breast cancer
• ER stress
• ER-phagy
• Nutrition deprivation
• Tamoxifen

• 67/06/2022-DDI/BMS and 5/7/1745/CH/Adhoc/RBMCH-2021 Indian Council of Medical Research
• CRG/2022/004934 Department of Science and Technology, Ministry of Science and Technology, India

• androgen deprivation
• autophagy
• cancer
• carcinogenesis
• chemotherapy
• prostate
• radiation
• therapy

• Helse Sør-Øst RHF

• Apoptosis
• Autophagy
• Cancer immunotherapy
• Immune system
• Immune tolerance

• Humans
• Neoplasms/immunology
• Neoplasms/therapy
• Neoplasms/pathology
• Autophagy/immunology
• Autophagy/drug effects
• Immunotherapy/methods
• Tumor Escape
• Animals
• Adaptive Immunity
• Cell Death/immunology
• Immunity, Innate

• DNA damage
• DNA damage response
• DNA double-strand breaks
• genome instability
• oxidative DNA damage
• replication stress
• structure-specific nucleases

• Humans
• DNA Replication
• DNA Repair
• DNA Damage
• Endonucleases/metabolism
• Genomic Instability
• DNA
• Nucleotides

• R01 CA139429 NCI NIH HHS
• R01 CA205224 NCI NIH HHS
• R01 CA139429 NIH HHS

• targeted therapies
• bile duct cancer

• angiogenesis
• autophagy
• cancer biology
• cancer management
• drug design
• signal transduction

• Anticancer
• Apoptosis
• Autophagy
• Molecular mechanism
• Pharmacology
• Phytochemicals

• ROS
• autophagy
• cancer
• phytochemicals

• Humans
• Female
• Phosphatidylinositol 3-Kinases/metabolism
• Proto-Oncogene Proteins c-akt/metabolism
• Ovarian Neoplasms/pathology
• Signal Transduction
• Autophagy
• Cell Line, Tumor
• Cell Proliferation
• Tumor Microenvironment

• Apoptosis
• Autophagy
• Glutathione
• Mitophagy
• Oxidative stress
• Reactive oxygen species

• Humans
• Reactive Oxygen Species/metabolism
• Oxidative Stress/physiology
• Autophagy
• Oxidation-Reduction
• Neoplasms/drug therapy
• Neoplasms/metabolism

• autophagy
• chemoresistance
• microRNAs
• pancreatic cancer

• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/genetics
• Carcinoma, Pancreatic Ductal/drug therapy
• Carcinoma, Pancreatic Ductal/genetics
• Autophagy/genetics
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Carcinogenesis

Alpinia katsumadai Hayata (AKH), a widely used traditional Chinese medicine, exerts various biological functions, including anti-inflammatory, antioxidant, anti-microbial and anti-asthmatic effects. However, studies on its anticancer activity and associated mechanisms are limited. The present study investigated the effects of ethanol extract from AKH on the viability of various human cancer and normal liver LX-2 cells using Cell Counting Kit-8 assay. Apoptosis was detected by Hoechst 33342/PI staining and Annexin-V-FITC/PI double staining. Autophagy was examined by Ad-GFP-LC3B transfection. The association between AKH-induced autophagy and apoptosis was investigated by pre-treatment of the cells with the autophagy inhibitors, 3-methyladenine (3MA) and bafilomycin A1 (Baf-A1), followed by treatment with AKH. The expression levels of cleaved poly(ADP-ribose) polymerase (PARP), caspase-8, caspase-3, caspase-9, phosphorylated (p-)AMP-activated protein kinase (AMPK), Akt, mTOR and p70S6K were examined using western blot analysis. The in vivo antitumor activity of AKH was investigated in nude mice bearing A549 lung cancer xenografts. The components of AKH were detected by liquid chromatography mass spectrometry-ion trap-time-of-flight mass spectrometry. The results revealed that AKH significantly inhibited the proliferation of various cancer cells with the half maximal inhibitory concentration (IC₅₀) values of 203–284 µg/ml; however, its inhibitory effect was much less prominent against normal liver LX-2 cells with an IC₅₀ value of 395 µg/ml. AKH markedly induced apoptosis and autophagy, and upregulated the protein expression of cleaved-caspase-3, caspase-8, caspase-9 and cleaved PARP in a concentration-dependent manner. Of note, the autophagy inhibitors (3MA and Baf-A1) significantly attenuated its pro-apoptotic effects on human pancreatic cancer Panc-28 and lung cancer A549 cells. Furthermore, AKH significantly increased the levels of p-AMPK, and decreased those of p-Akt, p-mTOR and p-p70S6K in Panc-28 and A549 cells. AKH markedly inhibited the growth of A549 tumor xenografts in vivo. In addition, a total of nine compounds were detected from AKH. The present study demonstrates that AKH markedly inhibits the growth and induces autophagy-related apoptosis in cancer cells by regulating the AMPK and Akt/mTOR/p70S6K signaling pathways. AKH and/or its active fractions may thus have potential to be developed as novel anticancer agents for clinical use.

• Alpinia katsumadai Hayata
• adenosine 5'‑monophosphate‑activated protein kinase
• apoptosis
• autophagy
• serine‑­threonine kinase/mammalian target of rapamycin/70‑kDa ribosomal protein S6 kinase signaling pathway

Lung cancer is the main cause of cancer-related deaths worldwide, mainly due to treatment resistance. For that reason, it is necessary to develop novel therapeutic strategies to overcome this phenomenon. The aim of our study was to design and characterize a synthetic anionophore, LAI-1, that would be able to efficiently disrupt lysosomal activity, leading to autophagy blockage, one of the most important resistance mechanisms in cancer cells. We confirmed that LAI-1 selectively localized in lysosomes, deacidifying them. This effect produced a blockage of autophagy, characterized by an abrogation of autophagosomes and lysosomes fusion. Moreover, LAI-1 produced cell death in lung cancer cells from different histological subtypes, inducing cytotoxicity more efficiently than other known autophagy inhibitors. Finally, LAI-1 was evaluated in combination therapy, showing sensitization to the first-line chemotherapeutic agent cisplatin. Altogether, LAI-1 is a novel late-stage autophagy inhibitor with potential therapeutic applications in tumors with cytoprotective autophagy.

Overcoming resistance is one of the most challenging features in current anticancer therapy. Autophagy is a cellular process that confers resistance in some advanced tumors, since it enables cancer cells to adapt to stressful situations, such as anticancer treatments. Hence, the inhibition of this cytoprotective autophagy leads to tumor cells sensitization and death. In this regard, we designed a novel potent anionophore compound that specifically targets lysosomes, called LAI-1 (late-stage autophagy inhibitor-1), and evaluated its role in blocking autophagy and its potential anticancer effects in three lung cancer cell lines from different histological subtypes. Compared to other autophagy inhibitors, such as chloroquine and 3-Methyladenine, the LAI-1 treatment induced more potent anticancer effects in all tested cancer cells. LAI-1 was able to efficiently target and deacidify lysosomes, while acidifying cytoplasmic pH. Consequently, LAI-1 efficiently blocked autophagy, indicated by the increased LC3-II/I ratio and p62/SQSTM1 levels. Moreover, no colocalization was observed between autophagosomes, marked with LC3 or p62/SQSTM1, and lysosomes, stained with LAMP-1, after the LAI-1 treatment, indicating the blockage of autophagolysosome formation. Furthermore, LAI-1 induced cell death by activating apoptosis (enhancing the cleavage of caspase-3 and PARP) or necrosis, depending on the cancer cell line. Finally, LAI-1 sensitized cancer cells to the first-line chemotherapeutic agent cisplatin. Altogether, LAI-1 is a new late-stage autophagy inhibitor that causes lysosomal dysfunction and the blockage of autophagolysosome formation, as well as potently induces cancer cell death and sensitization to conventional treatments at lower concentrations than other known autophagy inhibitors, appearing as a potential new therapeutic approach to overcome cancer resistance.

With a rich abundance of natural polyphenols, green tea has become one of the most popular and healthiest nonalcoholic beverages being consumed worldwide. Epigallocatechin-3-gallate (EGCG) is the predominant catechin found in green tea, which has been shown to promote numerous health benefits, including metabolic regulation, antioxidant, anti-inflammatory, and anticancer. Clinical studies have also shown the inhibitory effects of EGCG on cancers of the male and female reproductive system, including ovarian, cervical, endometrial, breast, testicular, and prostate cancers. Autophagy is a natural, self-degradation process that serves important functions in both tumor suppression and tumor cell survival. Naturally derived products have the potential to be an effective and safe alternative in balancing autophagy and maintaining homeostasis during tumor development. Although EGCG has been shown to play a critical role in the suppression of multiple cancers, its role as autophagy modulator in cancers of the male and female reproductive system remains to be fully discussed. Herein, we aim to provide an overview of the current knowledge of EGCG in targeting autophagy and its related signaling mechanism in reproductive cancers. Effects of EGCG on regulating autophagy toward reproductive cancers as a single therapy or cotreatment with other chemotherapies will be reviewed and compared. Additionally, the underlying mechanisms and crosstalk of EGCG between autophagy and other cellular processes, such as reactive oxidative stress, ER stress, angiogenesis, and apoptosis, will be summarized. The present review will help to shed light on the significance of green tea as a potential therapeutic treatment for reproductive cancers through regulating autophagy.

Cancer is one of the main causes of death globally. Most of the molecular mechanisms underlying cancer are marked by complex aberrations that activate the critical cell-signaling pathways that play a pivotal role in cell metabolism, tumor development, cytoskeletal reorganization, and metastasis. The phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of the rapamycin (PI3K/AKT/mTOR) pathway is one of the main signaling pathways involved in carcinogenesis and metastasis. Autophagy, a cellular pathway that delivers cytoplasmic components to lysosomes for degradation, plays a dual role in cancer, as either a tumor promoter or a tumor suppressor, depending on the stage of the carcinogenesis. Statins are the group of drugs of choice to lower the level of low-density lipoprotein (LDL) cholesterol in the blood. Experimental and clinical data suggest the potential of statins in the treatment of cancer. In vitro and in vivo studies have demonstrated the molecular mechanisms through which statins inhibit the proliferation and metastasis of cancer cells in different types of cancer. The anticancer properties of statins have been shown to result in the suppression of tumor growth, the induction of apoptosis, and autophagy. This literature review shows the dual role of the autophagic process in cancer and the latest scientific evidence related to the inducing effect exerted by statins on autophagy, which could explain their anticancer potential.

• Autophagy
• Cancer
• Homeostasis
• Hypoxia

Chemotherapy resistance is a common occurrence during cancer treatment that cancer researchers are attempting to understand and overcome. Mitochondria are a crucial intracellular signaling core that are becoming important determinants of numerous aspects of cancer genesis and progression, such as metabolic reprogramming, metastatic capability, and chemotherapeutic resistance. Mitophagy, or selective autophagy of mitochondria, can influence both the efficacy of tumor chemotherapy and the degree of drug resistance. Regardless of the fact that mitochondria are well-known for coordinating ATP synthesis from cellular respiration in cellular bioenergetics, little is known its mitophagy regulation in chemoresistance. Recent advancements in mitochondrial research, mitophagy regulatory mechanisms, and their implications for our understanding of chemotherapy resistance are discussed in this review.

Cancer chemotherapy resistance is one of the most critical obstacles in cancer therapy. One of the well-known mechanisms of chemotherapy resistance is the change in the mitochondrial death pathways which occur when cells are under stressful situations, such as chemotherapy. Mitophagy, or mitochondrial selective autophagy, is critical for cell quality control because it can efficiently break down, remove, and recycle defective or damaged mitochondria. As cancer cells use mitophagy to rapidly sweep away damaged mitochondria in order to mediate their own drug resistance, it influences the efficacy of tumor chemotherapy as well as the degree of drug resistance. Yet despite the importance of mitochondria and mitophagy in chemotherapy resistance, little is known about the precise mechanisms involved. As a consequence, identifying potential therapeutic targets by analyzing the signal pathways that govern mitophagy has become a vital research goal. In this paper, we review recent advances in mitochondrial research, mitophagy control mechanisms, and their implications for our understanding of chemotherapy resistance.

• Autophagy
• Glioblastoma
• Isoforms
• Tumor resistance

• Apoptosis
• Autophagosomes/genetics
• Autophagosomes/metabolism
• Autophagy
• Autophagy-Related Proteins/genetics
• Autophagy-Related Proteins/metabolism
• Glioma/genetics
• Glioma/metabolism
• Glioma/therapy
• Humans
• Neoplasm Proteins/metabolism

• No. 075-15-2020-926 Ministry of Science and Higher Education of the Russian Federation

• Autophagy
• Cancer therapy
• Lung cancer
• NSCLS
• Signaling

• Autophagy
• Carcinoma, Non-Small-Cell Lung/genetics
• Carcinoma, Non-Small-Cell Lung/metabolism
• Carcinoma, Non-Small-Cell Lung/therapy
• Humans
• Lung Neoplasms/genetics
• Lung Neoplasms/metabolism
• Lung Neoplasms/therapy
• Neoplasm Proteins/genetics
• Neoplasm Proteins/metabolism
• Signal Transduction

• 502Z20199113 xiamen medical and health guidance project funding

Autophagy is the capability of cells to dismantle and recycle parts of themselves. This process is closely intertwined with other crucial cell functions, such as growth and control of metabolism. Autophagy is oftentimes dysregulated in cancer and offers established and advanced tumors protection against a lack of nutrients and an advantage regarding proliferation. This review will present an overview of the basics of human autophagy, its dysregulation in cancer, and approaches to target autophagy in cancer treatment in recent and current clinical trials as well as new findings of preclinical research.

Autophagy is a crucial general survival tactic of mammalian cells. It describes the capability of cells to disassemble and partially recycle cellular components (e.g., mitochondria) in case they are damaged and pose a risk to cell survival or simply if their resources are urgently needed elsewhere at the time. Autophagy-associated pathomechanisms have been increasingly recognized as important disease mechanisms in non-malignant (neurodegeneration, diffuse parenchymal lung disease) and malignant conditions alike. However, the overall consequences of autophagy for the organism depend particularly on the greater context in which autophagy occurs, such as the cell type or whether the cell is proliferating. In cancer, autophagy sustains cancer cell survival under challenging, i.e., resource-depleted, conditions. However, this leads to situations in which cancer cells are completely dependent on autophagy. Accordingly, autophagy represents a promising yet complex target in cancer treatment with therapeutically induced increase and decrease of autophagic flux as important therapeutic principles.

• autophagy
• cancer
• glutamine
• hydroxychloroquine
• mitophagy
• reverse Warburg effect

• Autophagy
• Autophagy modulators
• Chemotherapy
• Cholangiocarcinoma

• cancer
• gene therapy

• AMPK
• Autophagy
• Colorectal cancer
• Lomitapide
• PP2A inhibitor

Vascular calcification is a closely linked to cardiovascular diseases, such as atherosclerosis, chronic kidney disease, diabetes, hypertension and aging. The extent of vascular calcification is closely correlate with adverse clinical events and cardiovascular all-cause mortality. The role of autophagy in vascular calcification is complex with many mechanistic unknowns.

In this review, we analyze the current known mechanisms of autophagy in vascular calcification and discuss the theoretical advantages of targeting autophagy as an intervention against vascular calcification.

Here we summarize the functional link between vascular calcification and autophagy in both animal models of and human cardiovascular disease. Firstly, autophagy can reduce calcification by inhibiting the osteogenic differentiation of VSMCs related to ANCR, ERα, β-catenin, HIF-1a/PDK4, p62, miR-30b, BECN1, mTOR, SOX9, GHSR/ERK, and AMPK signaling. Conversely, autophagy can induce osteoblast differentiation and calcification as mediated by CREB, degradation of elastin, and lncRNA H19 and DUSP5 mediated ERK signaling. Secondly, autophagy also links apoptosis and vascular calcification through AMPK/mTOR/ULK1, Wnt/β-catenin and GAS6/AXL synthesis, as apoptotic cells become the nidus for calcium-phosphate crystal deposition. The failure of mitophagy can activate Drp1, BNIP3, and NR4A1/DNA‑PKcs/p53 mediated intrinsic apoptotic pathways, which have been closely linked to the formation of vascular calcification. Additionally, autophagy also plays a role in osteogenesis by regulating vascular calcification, which in turn regulates expression of proteins related to bone development, such as osteocalcin, osteonectin, etc. and regulated by mTOR, EphrinB2 and RhoA. Furthermore, autophagy also promotes vitamin K2-induced MC3T3 E1 osteoblast differentiation and FGFR4/FGF18- and JNK/complex VPS34–beclin-1-related bone mineralization via vascular calcification.

The interaction between autophagy and vascular calcification are complicated, with their interaction affected by the disease process, anatomical location, and the surrounding microenvironment. Autophagy activation in existent cellular damage is considered protective, while defective autophagy in normal cells result in apoptotic activation. Identifying and maintaining cells at the delicate line between these two states may hold the key to reducing vascular calcification, in which autophagy associated clinical strategy could be developed.

• AMPK/mTOR
• Autophagy/mitophagy
• EphrinB2
• GAS6/AXL
• HIF-1a/PDK4
• Osteoblastic differentiation of VSMCs
• Osteogenesis
• Vascular calcification

Breast cancer is the second leading cause of cancer-related death in women in the United States. The Akt signaling pathway is deregulated in approximately 70% of patients with breast cancer. While targeting Akt is an effective therapeutic strategy for the treatment of breast cancer, there are several members in the Akt family that play distinct roles in breast cancer. However, the function of Akt isoforms depends on many factors. This review analyzes current progress on the isoform-specific functions of Akt isoforms in breast cancer.

Akt, also known as protein kinase B (PKB), belongs to the AGC family of protein kinases. It acts downstream of the phosphatidylinositol 3-kinase (PI3K) and regulates diverse cellular processes, including cell proliferation, cell survival, metabolism, tumor growth and metastasis. The PI3K/Akt signaling pathway is frequently deregulated in breast cancer and plays an important role in the development and progression of breast cancer. There are three closely related members in the Akt family, namely Akt1(PKBα), Akt2(PKBβ) and Akt3(PKBγ). Although Akt isoforms share similar structures, they exhibit redundant, distinct as well as opposite functions. While the Akt signaling pathway is an important target for cancer therapy, an understanding of the isoform-specific function of Akt is critical to effectively target this pathway. However, our perception regarding how Akt isoforms contribute to the genesis and progression of breast cancer changes as we gain new knowledge. The purpose of this review article is to analyze current literatures on distinct functions of Akt isoforms in breast cancer.

• AGC kinase
• Akt isoforms
• autophagy
• breast cancer initiation and progression
• cell proliferation
• metabolism
• metastasis
• regulation
• senescence
• tumorigenesis

Tea is one of the most popular and widely consumed beverages worldwide, and possesses numerous potential health benefits. Herbal teas are well-known to contain an abundance of polyphenol antioxidants and other ingredients, thereby implicating protection and treatment against various ailments, and maintaining overall health in humans, although their mechanisms of action have not yet been fully identified. Autophagy is a conserved mechanism present in organisms that maintains basal cellular homeostasis and is essential in mediating the pathogenesis of several diseases, including cancer, type II diabetes, obesity, and Alzheimer’s disease. The increasing prevalence of these diseases, which could be attributed to the imbalance in the level of autophagy, presents a considerable challenge in the healthcare industry. Natural medicine stands as an effective, safe, and economical alternative in balancing autophagy and maintaining homeostasis. Tea is a part of the diet for many people, and it could mediate autophagy as well. Here, we aim to provide an updated overview of popular herbal teas’ health-promoting and disease healing properties and in-depth information on their relation to autophagy and its related signaling molecules. The present review sheds more light on the significance of herbal teas in regulating autophagy, thereby improving overall health.

• autophagy
• cancer
• herbal tea
• inflammation
• metabolic disorders
• neurodegenerative diseases
• oxidative stress
• phytochemicals
• phytotherapy

• Norcantharidin (NCTD)
• apoptosis
• autophagy
• non-small cell lung cancer (NSCLC)

• anticancer
• apoptosis
• autophagy
• pharmacology
• phytochemicals

Colorectal cancer (CRC) represents a heterogeneous population of tumor cells and cancer stem cells (CSCs) where CSCs are postulated to resist the chemotherapy, and support cancer malignancy. Eliminating CSC can therefore improve CRC therapy and patient survival; however, such strategies have not yielded the desired outcome. Inhibiting autophagy has shown promise in suppressing therapy resistance; however, current autophagy inhibitors have failed in the clinical trials. In the current study, we provided data supporting the efficacy of 36-077, a potent inhibitor of PIK3C3/VPS34, in inhibiting autophagy to kill the CSC to promote the efficacy of colon cancer therapy.

Background: Despite recent advances in therapies, resistance to chemotherapy remains a critical problem in the clinical management of colorectal cancer (CRC). Cancer stem cells (CSCs) play a central role in therapy resistance. Thus, elimination of CSCs is crucial for effective CRC therapy; however, such strategies are limited. Autophagy promotes resistance to cancer therapy; however, whether autophagy protects CSCs to promote resistance to CRC-therapy is not well understood. Moreover, specific and potent autophagy inhibitors are warranted as clinical trials with hydroxychloroquine have not been successful. Methods: Colon cancer cells and tumoroids were used. Fluorescent reporter-based analysis of autophagy flux, spheroid and side population (SP) culture, and qPCR were done. We synthesized 36-077, a potent inhibitor of PIK3C3/VPS34 kinase, to inhibit autophagy. Combination treatments were done using 5-fluorouracil (5-FU) and 36-077. Results: The 5-FU treatment induced autophagy only in a subset of the treated colon cancer. These autophagy-enriched cells also showed increased expression of CSC markers. Co-treatment with 36-077 significantly improved efficacy of the 5-FU treatment. Mechanistic studies revealed that combination therapy inhibited GSK-3β/Wnt/β-catenin signaling to inhibit CSC population. Conclusion: Autophagy promotes resistance to CRC-therapy by specifically promoting GSK-3β/Wnt/β-catenin signaling to promote CSC survival, and 36-077, a PIK3C3/VPS34 inhibitor, helps promote efficacy of CRC therapy.

• 5-FloroUracil
• PI3KC3
• autophagy
• cancer stem cells
• chemoresistance

• R01 DK124095 NIDDK NIH HHS
• I01 BX002761 BLRD VA
• I01 BX002086 BLRD VA
• CA216746 NIH HHS
• P30 GM127200 NIGMS NIH HHS
• R21 CA216746 NCI NIH HHS

• Autophagy
• Beclin-1
• HCC
• HCV

• Autophagy/genetics
• Beclin-1/genetics
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/virology
• Egypt
• Female
• Gene Expression
• Hepatitis C/complications
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Liver Neoplasms/virology
• Male
• Neoplasm Grading
• Prognosis
• Survival Rate

Accumulating studies have demonstrated that autophagy plays an important role in hepatocellular carcinoma (HCC). We aimed to construct a prognostic model based on autophagy-related genes (ARGs) to predict the survival of HCC patients.

Differentially expressed ARGs were identified based on the expression data from The Cancer Genome Atlas and ARGs of the Human Autophagy Database. Univariate Cox regression analysis was used to identify the prognosis-related ARGs. Multivariate Cox regression analysis was performed to construct the prognostic model. Receiver operating characteristic (ROC), Kaplan-Meier curve, and multivariate Cox regression analyses were performed to test the prognostic value of the model. The prognostic value of the model was further confirmed by an independent data cohort obtained from the International Cancer Genome Consortium (ICGC) database.

A total of 34 prognosis-related ARGs were selected from 62 differentially expressed ARGs identified in HCC compared with noncancer tissues. After analysis, a novel prognostic model based on ARGs (PRKCD, BIRC5, and ATIC) was constructed. The risk score divided patients into high- or low-risk groups, which had significantly different survival rates. Multivariate Cox analysis indicated that the risk score was an independent risk factor for survival of HCC after adjusting for other conventional clinical parameters. ROC analysis showed that the predictive value of this model was better than that of other conventional clinical parameters. Moreover, the prognostic value of the model was further confirmed in an independent cohort from ICGC patients.

The prognosis-related ARGs could provide new perspectives on HCC, and the model should be helpful for predicting the prognosis of HCC patients.

It is challenging to overcome the low response rate of everolimus in the treatment of patients with hepatocellular carcinoma (HCC). To overcome this challenge, we combined everolimus with Ku0063794, the inhibitor of mTORC1 and mTORC2, to achieve higher anticancer effects. However, the precise mechanism for the synergistic effects is not clearly understood yet. To achieve this aim, the miRNAs were selected that showed the most significant variation in expression according to the mono- and combination therapy of everolimus and Ku0063794. Subsequently, the roles of specific miRNAs were determined in the processes of the treatment modalities. Compared to individual monotherapies, the combination therapy significantly reduced viability, increased apoptosis, and reduced autophagy in HepG2 cells. The combination therapy led to significantly lower expression of miR-4790-3p and higher expression of zinc finger protein225 (ZNF225)—the predicted target of miR-4790-3p. The functional study of miR-4790-3p and ZNF225 revealed that regarding autophagy, miR-4790-3p promoted it, while ZNF225 inhibited it. In addition, regarding apoptosis, miR-4790-3p inhibited it, while ZNF225 promoted it. It was also found that HCC tissues were characterized by higher expression of miR-4790-3p and lower expression of ZNF225; HCC tissues were also characterized by higher autophagic flux. We, thus, conclude that the potentiated anticancer effect of the everolimus and Ku0063794 combination therapy is strongly associated with reduced autophagy resulting from diminished expression of miR-4790-3p, as well as higher expression of ZNF225.

• ZNF225
• autophagy
• hepatocellular carcinoma
• mTOR inhibitor
• miR-4790-3p

• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Apoptosis/genetics
• Autophagy/drug effects
• Autophagy/genetics
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Cell Line, Tumor
• Cell Survival/drug effects
• Cell Survival/genetics
• Drug Synergism
• Early Growth Response Protein 1/genetics
• Early Growth Response Protein 1/metabolism
• Enzyme Inhibitors/pharmacology
• Everolimus/pharmacology
• Gene Expression Regulation, Neoplastic/drug effects
• Hep G2 Cells
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors
• Mechanistic Target of Rapamycin Complex 1/metabolism
• Mechanistic Target of Rapamycin Complex 2/antagonists & inhibitors
• Mechanistic Target of Rapamycin Complex 2/metabolism
• MicroRNAs/genetics
• Morpholines/pharmacology
• Pyrimidines/pharmacology

• autophagy
• cancer cells
• cell death
• cell survival
• human diseases
• oncoviruses

• U54 CA221208 NCI NIH HHS