scholarly journals AMPK-Mediated Metabolic Switching Is High Effective for Phytochemical Levo-Tetrahydropalmatine (L-THP) to Reduce Hepatocellular Carcinoma Tumor Growth

Metabolites ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 811
Author(s):  
Xunzhe Yin ◽  
Wenbo Li ◽  
Jiaxin Zhang ◽  
Wenjing Zhao ◽  
Huaxing Cai ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Metabolism ◽  
Adenosine Monophosphate ◽  
Tumor Promoter ◽  
Autophagic Flux ◽  
Cancer Subtypes ◽  
Metabolic Switching ◽  
Alternative Approach ◽  
Cancer Cell Metabolism ◽  
First Time

Targeting cancer cell metabolism has been an attractive approach for cancer treatment. However, the role of metabolic alternation in cancer is still unknown whether it functions as a tumor promoter or suppressor. Applying the cancer gene-metabolism integrative network model, we predict adenosine monophosphate-activated protein kinase (AMPK) to function as a central hub of metabolic landscape switching in specific liver cancer subtypes. For the first time, we demonstrate that the phytochemical levo-tetrahydropalmatine (L-THP), a Corydalis yanhusuo-derived clinical drug, as an AMPK activator via autophagy-mediated metabolic switching could kill the hepatocellular carcinoma HepG2 cells. Mechanistically, L-THP promotes the autophagic response by activating the AMPK-mTOR-ULK1 and the ROS-JNK-ATG cascades and impairing the ERK/AKT signaling. All these processes ultimately synergize to induce the decreased mitochondrial oxidative phosphorylation (OXPHOS) and mitochondrial damage. Notably, silencing AMPK significantly inhibits the autophagic flux and recovers the decreased OXPHOS metabolism, which results in HepG2 resistance to L-THP treatment. More importantly, L-THP potently reduces the growth of xenograft HepG2 tumor in nude mice without affecting other organs. From this perspective, our findings support the conclusion that metabolic change is an alternative approach to influence the development of HCC.

scholarly journals PIWIL1 governs the crosstalk of cancer cell metabolism and immunosuppressive microenvironment in hepatocellular carcinoma

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Ning Wang ◽  
Hor-Yue Tan ◽  
Yuanjun Lu ◽  
Yau-Tuen Chan ◽  
Di Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Fatty Acid ◽  
Tumor Microenvironment ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Immune Cell ◽  
Cell Metabolism ◽  
Cancer Cell Metabolism ◽  
Immune Cell Response ◽  
Hcc Cells

AbstractAltered energy metabolism of cancer cells shapes the immune cell response in the tumor microenvironment that facilitates tumor progression. Herein, we reported the novel of tumor cell-expressed Piwi Like RNA-Mediated Gene Silencing 1 (PIWIL1) in mediating the crosstalk of fatty acid metabolism and immune response of human hepatocellular carcinoma (HCC). PIWIL1 expression in HCC was increased compared to normal hepatic tissues and was positively correlated with the proliferation rate of HCC cell lines. PIWIL1 overexpression accelerated in vitro proliferation and in vivo growth of HCC tumors, while PIWIL1 knockdown showed opposite effects. PIWIL1 increased oxygen consumption and energy production via fatty acid metabolism without altering aerobic glycolysis. Inhibition of fatty acid metabolism abolished PIWIL1-induced HCC proliferation and growth. RNA-seq analysis revealed that immune system regulation might be involved, which was echoed by the experimental observation that PIWIL1-overexpressing HCC cells attracted myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment. MDSCs depletion reduced the proliferation and growth of PIWIL1-overexpressing HCC tumors. Complement C3, whose secretion was induced by PIWIL1 in HCC cells, mediates the interaction of HCC cells with MDSCs by activated p38 MAPK signaling in MDSCs, which in turn initiated expression of immunosuppressive cytokine IL10. Neutralizing IL10 secretion reduced the immunosuppressive activity of MDSCs in the microenvironment of PIWIL1-overexpressing HCC. Taken together, our study unraveled the critical role of PIWIL1 in initiating the interaction of cancer cell metabolism and immune cell response in HCC. Tumor cells-expressed PIWIL1 may be a potential target for the development of novel HCC treatment.

scholarly journals HMGB1 Promotes Resistance to Doxorubicin in Human Hepatocellular Carcinoma Cells by Inducing Autophagy via the AMPK/mTOR Signaling Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Junhua Li ◽  
Wei Zhou ◽  
Qiang Mao ◽  
Dandan Gao ◽  
Lin Xiong ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Signaling Pathway ◽  
High Mobility ◽  
Adenosine Monophosphate ◽  
Mtor Signaling ◽  
Autophagic Flux ◽  
Mtor Signaling Pathway ◽  
Acquired Drug Resistance ◽  
Hmgb1 Expression

Chemoresistance remains as a major hindrance in the treatment of hepatocellular carcinoma (HCC). High mobility group box protein 1 (HMGB1) enhances autophagic flux and protects tumor cells from apoptosis, which results in acquired drug resistance. However, the exact mechanisms underlying HMGB1-modulated autophagy in HCC chemoresistance remain to be defined. In the present study, we found that administration of doxorubicin (DOX) significantly promoted HMGB1 expression and induced HMGB1 cytoplasmic translocation in human HCC cell lines BEL7402 and SMMC7721, which enhanced autophagy that contributes to protecting HCC cells from apoptosis and increasing drug resistance. Moreover, we observed HMGB1 translocation and elevation of autophagy in DOX-resistant BEL7402 and SMMC7721 cells. Additionally, inhibition of HMGB1 and autophagy increased the sensitivities of BEL-7402 and SMMC-7721 cells to DOX and re-sensitized their DOX-resistant cells. Subsequently, we confirmed with HMGB1 regulated autophagy by activating the 5ʹ adenosine monophosphate-activated protein kinase (AMPK)/mTOR pathway. In summary, our results indicate that HMGB1 promotes acquired DOX resistance in DOX-treated BEL7402 and SMMC7721 cells by enhancing autophagy through the AMPK/mTOR signaling pathway. These findings provide the proof-of-concept that HMGB1 inhibitors might be an important targeted treatment strategy for HCC.

Mapping the Heart

2010 ◽  
Vol 18 (4) ◽  
pp. 6-8
Author(s):  
Stephen W. Carmichael
Keyword(s):  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
G Protein Coupled Receptors ◽  
Receptor Subtypes ◽  
Cardiac Muscle Cells ◽  
Guanine Nucleotide Binding Protein ◽  
The Common ◽  
Guanine Nucleotide Binding ◽  
First Time ◽  
G Protein Coupled

Some of the receptors on the surface of cardiac muscle cells (cardiomyocytes) mediate the response of these cells to catecholamines by causing the production of the common second messenger cyclic adenosine monophosphate (cAMP). An example of such receptors are the β1- and β2-adrenergic receptors (βARs) that are heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors. Selective stimulation of these two receptor subtypes leads to distinct physiological and pathophysiological responses, but their precise location on the surface of cardiomyocytes has not been correlated with these responses. In an ingenious combination of techniques, Viacheslav Nikolaev, Alexey Moshkov, Alexander Lyon, Michele Miragoli, Pavel Novak, Helen Paur, Martin Lohse, Yuri Korchev, Sian Harding, and Julia Gorelik have mapped the function of these receptors for the first time.

scholarly journals Metabolic Effects of Recurrent Genetic Aberrations in Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 396
Author(s):  
Timon A. Bloedjes ◽  
Guus de Wilde ◽  
Jeroen E. J. Guikema
Keyword(s):  
Multiple Myeloma ◽  
Cell Metabolism ◽  
Chromosomal Rearrangements ◽  
Chromosomal Translocations ◽  
Metabolic Effects ◽  
Aberrant Expression ◽  
Metabolic Functions ◽  
Complex Chromosomal Rearrangements ◽  
Cancer Cell Metabolism ◽  
The Many

Oncogene activation and malignant transformation exerts energetic, biosynthetic and redox demands on cancer cells due to increased proliferation, cell growth and tumor microenvironment adaptation. As such, altered metabolism is a hallmark of cancer, which is characterized by the reprogramming of multiple metabolic pathways. Multiple myeloma (MM) is a genetically heterogeneous disease that arises from terminally differentiated B cells. MM is characterized by reciprocal chromosomal translocations that often involve the immunoglobulin loci and a restricted set of partner loci, and complex chromosomal rearrangements that are associated with disease progression. Recurrent chromosomal aberrations in MM result in the aberrant expression of MYC, cyclin D1, FGFR3/MMSET and MAF/MAFB. In recent years, the intricate mechanisms that drive cancer cell metabolism and the many metabolic functions of the aforementioned MM-associated oncogenes have been investigated. Here, we discuss the metabolic consequences of recurrent chromosomal translocations in MM and provide a framework for the identification of metabolic changes that characterize MM cells.

scholarly journals A Holistic Evolutionary and 3D Pharmacophore Modelling Study Provides Insights into the Metabolism, Function, and Substrate Selectivity of the Human Monocarboxylate Transporter 4 (hMCT4)

2021 ◽  
Vol 22 (6) ◽  
pp. 2918
Author(s):  
Eleni Papakonstantinou ◽  
Dimitrios Vlachakis ◽  
Trias Thireou ◽  
Panayiotis G. Vlachoyiannopoulos ◽  
Elias Eliopoulos
Keyword(s):  
Cancer Cell ◽  
Structural Characteristics ◽  
Cell Metabolism ◽  
Intracellular Localization ◽  
Selective Inhibition ◽  
Monocarboxylate Transporter ◽  
Cancer Drug ◽  
Pharmacophore Modelling ◽  
Anti Cancer ◽  
Cancer Cell Metabolism

Monocarboxylate transporters (MCTs) are of great research interest for their role in cancer cell metabolism and their potential ability to transport pharmacologically relevant compounds across the membrane. Each member of the MCT family could potentially provide novel therapeutic approaches to various diseases. The major differences among MCTs are related to each of their specific metabolic roles, their relative substrate and inhibitor affinities, the regulation of their expression, their intracellular localization, and their tissue distribution. MCT4 is the main mediator for the efflux of L-lactate produced in the cell. Thus, MCT4 maintains the glycolytic phenotype of the cancer cell by supplying the molecular resources for tumor cell proliferation and promotes the acidification of the extracellular microenvironment from the co-transport of protons. A promising therapeutic strategy in anti-cancer drug design is the selective inhibition of MCT4 for the glycolytic suppression of solid tumors. A small number of studies indicate molecules for dual inhibition of MCT1 and MCT4; however, no selective inhibitor with high-affinity for MCT4 has been identified. In this study, we attempt to approach the structural characteristics of MCT4 through an in silico pipeline for molecular modelling and pharmacophore elucidation towards the identification of specific inhibitors as a novel anti-cancer strategy.

scholarly journals Interactome Analysis of KIN (Kin17) Shows New Functions of This Protein

2021 ◽  
Vol 43 (2) ◽  
pp. 767-781
Author(s):  
Vanessa Pinatto Gaspar ◽  
Anelise Cardoso Ramos ◽  
Philippe Cloutier ◽  
José Renato Pattaro Junior ◽  
Francisco Ferreira Duarte Junior ◽  
...  
Keyword(s):  
Dna Replication ◽  
Protein Interactions ◽  
Ribosome Biogenesis ◽  
Cell Metabolism ◽  
Cell Types ◽  
Protein Protein Interactions ◽  
Cellular Mechanisms ◽  
Cancerous Cell ◽  
First Time

KIN (Kin17) protein is overexpressed in a number of cancerous cell lines, and is therefore considered a possible cancer biomarker. It is a well-conserved protein across eukaryotes and is ubiquitously expressed in all cell types studied, suggesting an important role in the maintenance of basic cellular function which is yet to be well determined. Early studies on KIN suggested that this nuclear protein plays a role in cellular mechanisms such as DNA replication and/or repair; however, its association with chromatin depends on its methylation state. In order to provide a better understanding of the cellular role of this protein, we investigated its interactome by proximity-dependent biotin identification coupled to mass spectrometry (BioID-MS), used for identification of protein–protein interactions. Our analyses detected interaction with a novel set of proteins and reinforced previous observations linking KIN to factors involved in RNA processing, notably pre-mRNA splicing and ribosome biogenesis. However, little evidence supports that this protein is directly coupled to DNA replication and/or repair processes, as previously suggested. Furthermore, a novel interaction was observed with PRMT7 (protein arginine methyltransferase 7) and we demonstrated that KIN is modified by this enzyme. This interactome analysis indicates that KIN is associated with several cell metabolism functions, and shows for the first time an association with ribosome biogenesis, suggesting that KIN is likely a moonlight protein.

scholarly journals Steroidal Saponins Isolated from the Rhizome of Dioscorea tokoro Inhibit Cell Growth and Autophagy in Hepatocellular Carcinoma Cells

Life ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 749
Author(s):  
Shinya Okubo ◽  
Tomoe Ohta ◽  
Yukihiro Shoyama ◽  
Takuhiro Uto
Keyword(s):  
Hepatocellular Carcinoma ◽  
Antiproliferative Activity ◽  
Caspase 3 ◽  
Carcinoma Cells ◽  
Parp Cleavage ◽  
Autophagic Flux ◽  
Steroidal Saponin ◽  
Steroidal Saponins ◽  
Active Compounds ◽  
Hepatocellular Carcinoma Cells

Our preliminary screening identified an extract from the rhizome of Dioscorea tokoro, which strongly suppressed the proliferation of HepG2 hepatocellular carcinoma cells and inhibited autophagy. This study aimed to isolate active compounds from the rhizome of D. tokoro that exert antiproliferative effects and inhibit autophagy. The bioassay-guided fractionation of the active fraction led to the isolation of two spirostan-type steroidal saponins, dioscin (1) and yamogenin 3-O-α-l-rhamnopyranosyl (1→4)-O-α-l-rhamnopyranosyl(1→2)-β-d-glucopyranoside (2), and the frostane-type steroidal saponin protodioscin (3) from the n-BuOH fraction. Furthermore, acid hydrolysis of 1 and 2 produced the aglycones diosgenin (4) and yamogenin (5), respectively. Compounds 1–5 suppressed proliferation of HepG2 cells. The analysis of structure-activity relationships indicated that the 25(R)-conformation, structures with a sugar moiety, and the spirostan-type aglycone moiety contributed to antiproliferative activity. Analysis of autophagy-related proteins demonstrated that 1–3 clearly increased the levels of both LC3-II and p62, implying that 1–3 deregulate the autophagic pathway by blocking autophagic flux, which results in p62 and LC3-II accumulation. In contrast, 1–3 did not significantly affect caspase-3 activation and PARP cleavage, suggesting that the antiproliferative activity of 1–3 occurred independently of caspase-3-mediated apoptosis. In summary, our study showed that 1–3, active compounds in the rhizome of D. tokoro, suppressed cell proliferation and autophagy, and might be potential agents for autophagy research and cancer chemoprevention.

scholarly journals Oncolytic Virotherapy: The Cancer Cell Side

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 939
Author(s):  
Marcelo Ehrlich ◽  
Eran Bacharach
Keyword(s):  
Viral Replication ◽  
Cancer Cell ◽  
Cell Metabolism ◽  
Tumor Development ◽  
Oncolytic Viruses ◽  
Oncogenic Signaling ◽  
Functional Connection ◽  
Immunity Genes ◽  
Cancer Cell Metabolism ◽  
Editing Process

Cell autonomous immunity genes mediate the multiple stages of anti-viral defenses, including recognition of invading pathogens, inhibition of viral replication, reprogramming of cellular metabolism, programmed-cell-death, paracrine induction of antiviral state, and activation of immunostimulatory inflammation. In tumor development and/or immunotherapy settings, selective pressure applied by the immune system results in tumor immunoediting, a reduction in the immunostimulatory potential of the cancer cell. This editing process comprises the reduced expression and/or function of cell autonomous immunity genes, allowing for immune-evasion of the tumor while concomitantly attenuating anti-viral defenses. Combined with the oncogene-enhanced anabolic nature of cancer-cell metabolism, this attenuation of antiviral defenses contributes to viral replication and to the selectivity of oncolytic viruses (OVs) towards malignant cells. Here, we review the manners by which oncogene-mediated transformation and tumor immunoediting combine to alter the intracellular milieu of tumor cells, for the benefit of OV replication. We also explore the functional connection between oncogenic signaling and epigenetic silencing, and the way by which restriction of such silencing results in immune activation. Together, the picture that emerges is one in which OVs and epigenetic modifiers are part of a growing therapeutic toolbox that employs activation of anti-tumor immunity for cancer therapy.

scholarly journals Cyclin B1 acts as a tumor microenvironment-related cancer promoter and prognostic biomarker in hepatocellular carcinoma

2021 ◽  
Vol 49 (5) ◽  
pp. 030006052110162
Author(s):  
Yangming Hou ◽  
Xin Wang ◽  
Junwei Wang ◽  
Xuemei Sun ◽  
Xinbo Liu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Microenvironment ◽  
Proportional Hazards ◽  
Enrichment Analysis ◽  
Gene Signature ◽  
Cyclin B1 ◽  
Cox Proportional Hazards ◽  
Gene Set Enrichment Analysis ◽  
Tumor Promoter ◽  
Protein Protein Interaction

Objectives The present study aimed to develop a gene signature based on the ESTIMATE algorithm in hepatocellular carcinoma (HCC) and explore possible cancer promoters. Methods The ESTIMATE and CIBERSORT algorithms were applied to calculate the immune/stromal scores and the proportion of tumor-infiltrating immune cells (TICs) in a cohort of HCC patients. The differentially expressed genes (DEGs) were screened by Cox proportional hazards regression analysis and protein–protein interaction (PPI) network construction. Cyclin B1 (CCNB1) function was verified using experiments. Results The stromal and immune scores were associated with clinicopathological factors and recurrence-free survival (RFS) in HCC patients. In total, 546 DEGs were up-regulated in low score groups, 127 of which were associated with RFS. CCNB1 was regarded as the most predictive factor closely related to prognosis of HCC and could be a cancer promoter. Gene Set Enrichment Analysis (GSEA) and CIBERSORT analyses indicated that CCNB1 levels influenced HCC tumor microenvironment (TME) immune activity. Conclusions The ESTIMATE signature can be used as a prognosis tool in HCC. CCNB1 is a tumor promoter and contributes to TME status conversion.

scholarly journals Crizotinib Resistance Mediated by Autophagy Is Higher in the Stem-Like Cell Subset in ALK-Positive Anaplastic Large Cell Lymphoma, and This Effect Is MYC-Dependent

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 181
Author(s):  
Chuquan Shang ◽  
Bardes Hassan ◽  
Moinul Haque ◽  
Yuqi Song ◽  
Jing Li ◽  
...  
Keyword(s):  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Cell Subset ◽  
Large Cell ◽  
Autophagic Flux ◽  
Cytoprotective Effect ◽  
Direct Role ◽  
Large Cell Lymphoma ◽  
Alk Positive ◽  
First Time

Previously it was shown that autophagy contributes to crizotinib resistance in ALK-positive anaplastic large cell lymphoma (ALK + ALCL). We asked if autophagy is equally important in two distinct subsets of ALK + ALCL, namely Reporter Unresponsive (RU) and Reporter Responsive (RR), of which RR cells display stem-like properties. Autophagic flux was assessed with a fluorescence tagged LC3 reporter and immunoblots to detect endogenous LC3 alongside chloroquine, an autophagy inhibitor. The stem-like RR cells displayed significantly higher autophagic response upon crizotinib treatment. Their exaggerated autophagic response is cytoprotective against crizotinib, as inhibition of autophagy using chloroquine or shRNA against BECN1 or ATG7 led to a decrease in their viability. In contrast, autophagy inhibition in RU resulted in minimal changes. Since the differential protein expression of MYC is a regulator of the RU/RR dichotomy and is higher in RR cells, we asked if MYC regulates the autophagy-mediated cytoprotective effect. Inhibition of MYC in RR cells using shRNA significantly blunted crizotinib-induced autophagic response and effectively suppressed this cytoprotective effect. In conclusion, stem-like RR cells respond with rapid and intense autophagic flux which manifests with crizotinib resistance. For the first time, we have highlighted the direct role of MYC in regulating autophagy and its associated chemoresistance phenotype in ALK + ALCL stem-like cells.

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