Targeting energy metabolism to eliminate cancer cells

Shahruzaman, S. H.; Fakurazi, Sharida; Maniam, Sandra

doi:10.2147/cmar.s167424

Cited by 26 publications

(15 citation statements)

References 99 publications

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“…During the last decade, a great attention has also been paid to energy metabolic reprogramming of cancer. However, cancer basic studies fail to reach a consistent conclusion on mitochondrial function in cancer energy metabolism [ 21 ]. The mtDEPs enriched in mitochondrial dysfunction pathway (Supplementary Figure 1 item 2) provided molecular markers of the abnormal energy metabolism between cancer tissues and control tissues, including ACO1 (fold change = 0.65, p = 0.006), AIFM1 (fold change = 1.58, p = 0.002), ATPAF1 (fold change = 1.90, p = 0.009), ATPAF2 (fold change = 1.54, p = 0.0001), BCL2 (fold change = 0.30, p = 0.00003), COX17 (fold change = 2.74, p = 0.004), COX4I1 (fold change = 1.51, p = 0.004), COX4I2 (fold change = 0.20, p = 0.0006), COX6C (fold change = 1.54, p = 0.005), COX7A2 (fold change = 1.54, p = 0.03), COX7A2L (fold change = 1.87, p = 0.005), CYCS (fold change = 2.42, p = 0.001), GPX7 (fold change = 1.66, p = 0.0002), HTRA2 (fold change = 1.57, p = 0.008), MAOB (fold change = 0.41, p = 0.0002), TXN2 (fold change = 1.52, p = 0.005), and UQCRH (fold change = 1.59, p = 0.01).…”

Section: Resultsmentioning

confidence: 99%

Signaling pathway network alterations in human ovarian cancers identified with quantitative mitochondrial proteomics

Zhan

2019

EPMA Journal

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Relevance Molecular network changes are the hallmark of the pathogenesis of ovarian cancers (OCs). Network-based biomarkers benefit for the effective treatment of OC. Purpose This study sought to identify key pathway–network alterations and network-based biomarkers for clarification of molecular mechanisms and treatment of OCs. Methods Ingenuity Pathway Analysis (IPA) platform was used to mine signaling pathway networks with 1198 human tissue mitochondrial differentially expressed proteins (mtDEPs) and compared those pathway network changes between OCs and controls. The mtDEPs in important cancer-related pathway systems were further validated with qRT-PCR and Western blot in OC cell models. Moreover, integrative analysis of mtDEPs and Cancer Genome Atlas (TCGA) data from 419 patients was used to identify hub molecules with molecular complex detection method. Hub molecule–based survival analysis and multiple multivariate regression analysis were used to identify survival-related hub molecules and hub molecule signature model. Results Pathway network analysis revealed 25 statistically significant networks, 192 canonical pathways, and 5 significant molecular/cellular function models. A total of 52 canonical pathways were activated or inhibited in cancer pathogenesis, including antigen presentation, mitochondrial dysfunction, GP6 signaling, EIF2 signaling, and glutathione-mediated detoxification. Of them, mtDEPs (TPM1, CALR, GSTP1, LYN, AKAP12, and CPT2) in those canonical pathway and molecular/cellular models were validated in OC cell models at the mRNA and protein levels. Moreover, 102 hub molecules were identified, and they were regulated by post-translational modifications and functioned in multiple biological processes. Of them, 62 hub molecules were individually significantly related to OC survival risk. Furthermore, multivariate regression analysis of 102 hub molecules identified significant seven hub molecule signature models (HIST1H2BK, ALB, RRAS2, HIBCH, EIF3E, RPS20, and RPL23A) to assess OC survival risks. Conclusion These findings provided the overall signaling pathway network profiling of human OCs; offered scientific data to discover pathway network-based cancer biomarkers for diagnosis, prognosis, and treatment of OCs; and clarify accurate molecular mechanisms and therapeutic targets. These findings benefit for the discovery of effective and reliable biomarkers based on pathway networks for OC predictive and personalized medicine. Electronic supplementary material The online version of this article (10.1007/s13167-019-00170-5) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Signaling pathway network alterations in human ovarian cancers identified with quantitative mitochondrial proteomics

Zhan

2019

EPMA Journal

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“…Modulating ATP availability might be an essential strategy in inducing cell resistance and sustaining cancer progression and growth (4). Recent findings have demonstrated that cancer cells take advantage of high OXPHOS, including leukemias, lymphomas, pancreatic ductal adenocarcinoma, melanoma, and endometrial carcinoma (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16), while mitochondria can modulate their morphology regulating the intrinsic apoptotic pathway and participating in the resistance of cancer cells to apoptotic stimuli (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Bioenergetics at the Onset of Drug Resistance in Hematological Malignancies: An Overview

et al. 2020

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The combined derangements in mitochondria network, function and dynamics can affect metabolism and ATP production, redox homeostasis and apoptosis triggering, contributing to cancer development in many different complex ways. In hematological malignancies, there is a strong relationship between cellular metabolism, mitochondrial bioenergetics, interconnections with supportive microenvironment and drug resistance. Lymphoma and chronic lymphocytic leukemia cells, e.g., adapt to intrinsic oxidative stress by increasing mitochondrial biogenesis. In other hematological disorders such as myeloma, on the contrary, bioenergetics changes, associated to increased mitochondrial fitness, derive from the adaptive response to drug-induced stress. In the bone marrow niche, a reverse Warburg effect has been recently described, consisting in metabolic changes occurring in stromal cells in the attempt to metabolically support adjacent cancer cells. Moreover, a physiological dynamic, based on mitochondria transfer, between tumor cells and their supporting stromal microenvironment has been described to sustain oxidative stress associated to proteostasis maintenance in multiple myeloma and leukemia. Increased mitochondrial biogenesis of tumor cells associated to acquisition of new mitochondria transferred by mesenchymal stromal cells results in augmented ATP production through increased oxidative phosphorylation (OX-PHOS), higher drug resistance, and resurgence after treatment. Accordingly, targeting mitochondrial biogenesis, electron transfer, mitochondrial DNA replication, or mitochondrial fatty acid transport increases therapy efficacy. In this review, we summarize selected examples of the mitochondrial derangements in hematological malignancies, which provide metabolic adaptation and apoptosis resistance, also supported by the crosstalk with tumor microenvironment. This field promises a rational design to improve target-therapy including the metabolic phenotype.

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“…These data indicate that the reprogramming of glycogen metabolism in MPC provides a source of energy contributing to the tumor cell survival. Like other targeted therapies being developed, anticancer agents targeted on GLUT1 and glucose metabolism associated enzymes have demonstrated promising anticancer activities [36-38]. Targeting inhibition of these glycogen metabolism enzymes might warrant consideration as possible anticancer therapies in future studies for colorectal MPCs.…”

Section: Discussionmentioning

confidence: 99%

Glucose Metabolic Reprogramming and Cell Proliferation Arrest in Colorectal Micropapillary Carcinoma

et al. 2019

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Background Micropapillary carcinoma (MPC) has been reported as an aggressive variant of colorectal carcinoma (CRC) associated with frequent lymphovascular invasion and poor outcome. Altered glycogen metabolism by metabolic reprogramming plays a critical role for cancer cell growth and survival. We aimed to investigate glucose metabolic reprogramming in colorectal MPC. Methods Immmunostains for Ki-67 and glucose transporter 1 (GLUT1) were performed on 10 colorectal MPCs. Real-time PCR analysis of expressions of GLUT1 and glycogen metabolizing enzymes: glycogen synthase (GYS1) and glycogen phosphorylase (PYGL) was performed on cultured monolayer and three-dimensional (3D) spheroid HCT116 colon cancer cells. Results GLUT1 was strongly expressed in MPC as compared to adjacent conventional glandular component, and was also significantly increased expression in 3D spheroids. Upregulation of GYS1 and PYGL was markedly increased in 3D spheroids. The proliferation rate (Ki-67) of MPC was significantly lower compared to conventional glandular component. The 3D spheroids showed increased cell cycle arrest. Our results demonstrate altered glycogen metabolism in colorectal MPC. Conclusion The reprogramming of glycogen metabolism in MPC provides a source of energy contributing to tumor cell survival in a low proliferation state. Targeting glucose-regulated metabolism may warrant consideration as possible MPC therapies.

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Targeting energy metabolism to eliminate cancer cells

Cited by 26 publications

References 99 publications

Signaling pathway network alterations in human ovarian cancers identified with quantitative mitochondrial proteomics

Signaling pathway network alterations in human ovarian cancers identified with quantitative mitochondrial proteomics

Mitochondrial Bioenergetics at the Onset of Drug Resistance in Hematological Malignancies: An Overview

Glucose Metabolic Reprogramming and Cell Proliferation Arrest in Colorectal Micropapillary Carcinoma

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