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Signaling Transduction in Cancer Metabolism

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (1 April 2023) | Viewed by 36820

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Prof. Dr. BuHyun Youn

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Department of Biological Sciences, Pusan National University, Busan 46241, Republic of Korea
Interests: brain tumor; glioblastoma; therapeutic resistance; cancer metabolism; signaling transduction; oncogene; radiotherapy
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Special Issue Information

Dear Colleagues,

Metabolic reprogramming is a major hallmark of cancer. Cancer cells exhibit aerobic glycolysis and high rates of anabolic activity, a phenotype known as the Warburg effect. Oncogenic signaling pathways mediate metabolic gene expression and the activities of metabolic enzymes to reprogram the cellular metabolism. Signal transduction in cancer cells controls cell growth and division, building blocks, and redox potentials for cancer progression. Recently, targeting signal transduction in cancer metabolism has emerged as one of the most prominent aspects of cancer treatment. Thus, it is crucial to understand how cancer cells regulate their metabolism by oncogenic signaling pathways. This can help to develop novel compounds designed to target the pathways in cancer cells. We invite articles related to the field of signaling pathways involved in glucose metabolism (e.g., Akt signaling, EGFR signaling, and HIF1 signaling), lipid metabolism (e.g., PPARγ/mTOR signaling and SREBP signaling), and amino acid metabolism (e.g., c-Myc signaling), as well as other minor metabolic processes, including redox homeostasis and nucleotide metabolism.

This Special Issue will cover preclinical and clinical studies targeting signal transduction pathways related to metabolism for cancer therapy as well as recent discoveries in the field of signaling transduction in cancer metabolism.

Prof. Dr. BuHyun Youn
Guest Editor

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Keywords

signal transduction
cancer metabolism
oncogenic signaling
metabolic reprogramming
cancer therapy

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Published Papers (10 papers)

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Research

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17 pages, 4995 KiB

Open AccessArticle

Metabolic Dysregulation Explains the Diverse Impacts of Obesity in Males and Females with Gastrointestinal Cancers

by Spencer R. Rosario, Bowen Dong, Yali Zhang, Hua-Hsin Hsiao, Emily Isenhart, Jianmin Wang, Erin M. Siegel, Arta M. Monjazeb, Dwight H. Owen, Prasenjit Dey, Fred K. Tabung, Daniel J. Spakowicz, William J. Murphy, Stephen Edge, Sai Yendamuri, Sami Ibrahimi, Jill M. Kolesar, Patsy H. McDonald, Deepak Vadehra, Michelle Churchman, Song Liu, Pawel Kalinski and Sarbajit Mukherjee Show full author list Hide full author list

Int. J. Mol. Sci. 2023, 24(13), 10847; https://doi.org/10.3390/ijms241310847 - 29 Jun 2023

Cited by 3 | Viewed by 3423

Abstract

The prevalence of obesity, defined as the body mass index (BMI) ≥ 30 kg/m², has reached epidemic levels. Obesity is associated with an increased risk of various cancers, including gastrointestinal ones. Recent evidence has suggested that obesity disproportionately impacts males and females with cancer, resulting in varied transcriptional and metabolic dysregulation. This study aimed to elucidate the differences in the metabolic milieu of adenocarcinomas of the gastrointestinal (GI) tract both related and unrelated to sex in obesity. To demonstrate these obesity and sex-related effects, we utilized three primary data sources: serum metabolomics from obese and non-obese patients assessed via the Biocrates MxP Quant 500 mass spectrometry-based kit, the ORIEN tumor RNA-sequencing data for all adenocarcinoma cases to assess the impacts of obesity, and publicly available TCGA transcriptional analysis to assess GI cancers and sex-related differences in GI cancers specifically. We applied and integrated our unique transcriptional metabolic pipeline in combination with our metabolomics data to reveal how obesity and sex can dictate differential metabolism in patients. Differentially expressed genes (DEG) analysis of ORIEN obese adenocarcinoma as compared to normal-weight adenocarcinoma patients resulted in large-scale transcriptional reprogramming (4029 DEGs, adj. p < 0.05 and |logFC| > 0.58). Gene Set Enrichment and metabolic pipeline analysis showed genes enriched for pathways relating to immunity (inflammation, and CD40 signaling, among others) and metabolism. Specifically, we found alterations to steroid metabolism and tryptophan/kynurenine metabolism in obese patients, both of which are highly associated with disease severity and immune cell dysfunction. These findings were further confirmed using the TCGA colorectal adenocarcinoma (CRC) and esophageal adenocarcinoma (ESCA) data, which showed similar patterns of increased tryptophan catabolism for kynurenine production in obese patients. These patients further showed disparate alterations between males and females when comparing obese to non-obese patient populations. Alterations to immune and metabolic pathways were validated in six patients (two obese and four normal weight) via CD8+/CD4+ peripheral blood mononuclear cell RNA-sequencing and paired serum metabolomics, which showed differential kynurenine and lipid metabolism, which corresponded with altered T-cell transcriptome in obese populations. Overall, obesity is associated with differential transcriptional and metabolic programs in various disease sites. Further, these alterations, such as kynurenine and tryptophan metabolism, which impact both metabolism and immune phenotype, vary with sex and obesity together. This study warrants further in-depth investigation into obesity and sex-related alterations in cancers that may better define biomarkers of response to immunotherapy. Full article

(This article belongs to the Special Issue Signaling Transduction in Cancer Metabolism)

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14 pages, 2595 KiB

Open AccessArticle

Anti-Metastatic Effect of Pyruvate Dehydrogenase Kinase 4 Inhibition in Bladder Cancer via the ERK, SRC, and JNK Pathways

by Eun Hye Lee, Jae-Wook Chung, Eunji Sung, Bo Hyun Yoon, Minji Jeon, Song Park, So Young Chun, Jun Nyung Lee, Bum Soo Kim, Hyun Tae Kim, Tae Hwan Kim, Seock Hwan Choi, Eun Sang Yoo, Tae Gyun Kwon, Ho Won Kang, Wun-Jae Kim, Seok Joong Yun, Sangkyu Lee and Yun-Sok Ha

Int. J. Mol. Sci. 2022, 23(21), 13240; https://doi.org/10.3390/ijms232113240 - 31 Oct 2022

Cited by 8 | Viewed by 2342

Abstract

Bladder cancer is a common global cancer with a high percentage of metastases and high mortality rate. Thus, it is necessary to identify new biomarkers that can be helpful in diagnosis. Pyruvate dehydrogenase kinase 4 (PDK4) belongs to the PDK family and plays an important role in glucose utilization in living organisms. In the present study, we evaluated the role of PDK4 in bladder cancer and its related protein changes. First, we observed elevated PDK4 expression in high-grade bladder cancers. To screen for changes in PDK4-related proteins in bladder cancer, we performed a comparative proteomic analysis using PDK4 knockdown cells. In bladder cancer cell lines, PDK4 silencing resulted in a lower rate of cell migration and invasion. In addition, a PDK4 knockdown xenograft model showed reduced bladder cancer growth in nude mice. Based on our results, PDK4 plays a critical role in the metastasis and growth of bladder cancer cells through changes in ERK, SRC, and JNK. Full article

(This article belongs to the Special Issue Signaling Transduction in Cancer Metabolism)

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15 pages, 2514 KiB

Open AccessArticle

Vitamin C Suppresses Pancreatic Carcinogenesis through the Inhibition of Both Glucose Metabolism and Wnt Signaling

by Ji Hye Kim, Sein Hwang, Ji-Hye Lee, Se Seul Im and Jaekyoung Son

Int. J. Mol. Sci. 2022, 23(20), 12249; https://doi.org/10.3390/ijms232012249 - 14 Oct 2022

Cited by 9 | Viewed by 3019

Abstract

Cumulative studies have indicated that high-dose vitamin C has antitumor effects against a variety of cancers. However, the molecular mechanisms underlying these inhibitory effects against tumorigenesis and metastasis, particularly in relation to pancreatic cancer, are unclear. Here, we report that vitamin C at high concentrations impairs the growth and survival of pancreatic ductal adenocarcinoma (PDAC) cells by inhibiting glucose metabolism. Vitamin C was also found to trigger apoptosis in a caspase-independent manner. We further demonstrate that it suppresses the invasion and metastasis of PDAC cells by inhibiting the Wnt/β-catenin-mediated epithelial-mesenchymal transition (EMT). Taken together, our results suggest that vitamin C has therapeutic effects against pancreatic cancer. Full article

(This article belongs to the Special Issue Signaling Transduction in Cancer Metabolism)

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16 pages, 4999 KiB

Open AccessArticle

Lack of Oestrogen Receptor Expression in Breast Cancer Cells Does Not Correlate with Kisspeptin Signalling and Migration

by Udochi F. Azubuike, Claire L. Newton and Iman van den Bout

Int. J. Mol. Sci. 2022, 23(15), 8744; https://doi.org/10.3390/ijms23158744 - 6 Aug 2022

Viewed by 1955

Abstract

Kisspeptin is an anti-metastatic mediator in many cancer types, acting through its receptor, KISS1R. However, controversy remains regarding its role in breast cancer since both pro- and anti-metastatic roles have been ascribed to it. In KISS1R overexpressing triple-negative breast cancer (TNBC) cells, stimulation has been associated with increased invasion and MMP-9 expression, leading to the suggestion that hormone receptor status determines the metastatic effects of kisspeptin. To assess the veracity of this claim, we compared endogenous KISS1R signalling and physiological output in the hormone receptor-negative MDA-MB-231 and BT-20 cell lines after KP-10 (shortest active kisspeptin peptide) stimulation. MDA-MB-231 cells are metastatic when implanted in mice while BT-20 are not and remain epithelial-like. We show that both cell lines express KISS1R mRNA and respond to KP-10 by elevating calcium mobilisation. However, KP-10 stimulation induced migration of MDA-MB-231, but not BT-20 cells, in a calcium-dependent manner. Moreover, only BT-20 cells responded to KP-10 by increasing ERK phosphorylation in a β-arrestin-dependent manner. Interestingly, both cell lines displayed different complements of β-arrestin 1 and 2 expression. Overall, our data shows that, in TNBC, it is not universally true that kisspeptin/KISS1R stimulate migration or pro-metastatic behaviour, as divergent responses were observed in the two TNBC lines tested. Whether this divergence is related to the observed differences in β-arrestin complements warrants further investigation and may enable further stratification of the ability of kisspeptin to influence breast tumour behaviour. Full article

(This article belongs to the Special Issue Signaling Transduction in Cancer Metabolism)

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22 pages, 3414 KiB

Open AccessArticle

The C-Terminal Acidic Tail Modulates the Anticancer Properties of HMGB1

by Chloé Borde, Clémentine Dillard, Aurore L’Honoré, Frédérique Quignon, Marion Hamon, Christophe H. Marchand, Roberta Soares Faccion, Maurício G. S. Costa, Elodie Pramil, Annette K. Larsen, Michèle Sabbah, Stéphane D. Lemaire, Vincent Maréchal and Alexandre E. Escargueil

Int. J. Mol. Sci. 2022, 23(14), 7865; https://doi.org/10.3390/ijms23147865 - 17 Jul 2022

Cited by 2 | Viewed by 2272

Abstract

Energy metabolism reprogramming was recently listed as a hallmark of cancer. In this process, the switch from pyruvate kinase isoenzyme type M1 to pyruvate kinase isoenzyme type M2 (PKM2) is believed to play a crucial role. Interestingly, the activity of the active form of PKM2 can efficiently be inhibited by the high-mobility group box 1 (HMGB1) protein, leading to a rapid blockage of glucose-dependent aerobic respiration and cancer cell death. HMGB1 is a member of the HMG protein family. It contains two DNA-binding HMG-box domains and an acidic C-terminal tail capable of positively or negatively modulating its biological properties. In this work, we report that the deletion of the C-terminal tail of HMGB1 increases its activity towards a large panel of cancer cells without affecting the viability of normal immortalized fibroblasts. Moreover, in silico analysis suggests that the truncated form of HMGB1 retains the capacity of the full-length protein to interact with PKM2. However, based on the capacity of the cells to circumvent oxidative phosphorylation inhibition, we were able to identify either a cytotoxic or cytostatic effect of the proteins. Together, our study provides new insights in the characterization of the anticancer activity of HMGB1. Full article

(This article belongs to the Special Issue Signaling Transduction in Cancer Metabolism)

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Review

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25 pages, 1508 KiB

Open AccessReview

Interplay of Vitamin D and SIRT1 in Tissue-Specific Metabolism—Potential Roles in Prevention and Treatment of Non-Communicable Diseases Including Cancer

by Zsuzsanna Nemeth, Attila Patonai, Laura Simon-Szabó and István Takács

Int. J. Mol. Sci. 2023, 24(7), 6154; https://doi.org/10.3390/ijms24076154 - 24 Mar 2023

Cited by 9 | Viewed by 5621

Abstract

The importance of the prevention and control of non-communicable diseases, including obesity, metabolic syndrome, type 2 diabetes, cardiovascular diseases, and cancer, is increasing as a requirement of the aging population in developed countries and the sustainability of healthcare. Similarly, the 2013–2030 action plan of the WHO for the prevention and control of non-communicable diseases seeks these achievements. Adequate lifestyle changes, alone or with the necessary treatments, could reduce the risk of mortality or the deterioration of quality of life. In our recent work, we summarized the role of two central factors, i.e., appropriate levels of vitamin D and SIRT1, which are connected to adequate lifestyles with beneficial effects on the prevention and control of non-communicable diseases. Both of these factors have received increased attention in relation to the COVID-19 pandemic as they both take part in regulation of the main metabolic processes, i.e., lipid/glucose/energy homeostasis, oxidative stress, redox balance, and cell fate, as well as in the healthy regulation of the immune system. Vitamin D and SIRT1 have direct and indirect influence of the regulation of transcription and epigenetic changes and are related to cytoplasmic signaling pathways such as PLC/DAG/IP3/PKC/MAPK, MEK/Erk, insulin/mTOR/cell growth, proliferation; leptin/PI3K-Akt-mTORC1, Akt/NFĸB/COX-2, NFĸB/TNFα, IL-6, IL-8, IL-1β, and AMPK/PGC-1α/GLUT4, among others. Through their proper regulation, they maintain normal body weight, lipid profile, insulin secretion and sensitivity, balance between the pro- and anti-inflammatory processes under normal conditions and infections, maintain endothelial health; balance cell differentiation, proliferation, and fate; and balance the circadian rhythm of the cellular metabolism. The role of these two molecules is interconnected in the molecular network, and they regulate each other in several layers of the homeostasis of energy and the cellular metabolism. Both have a central role in the maintenance of healthy and balanced immune regulation and redox reactions; therefore, they could constitute promising targets either for prevention or as complementary therapies to achieve a better quality of life, at any age, for healthy people and patients under chronic conditions. Full article

(This article belongs to the Special Issue Signaling Transduction in Cancer Metabolism)

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29 pages, 1963 KiB

Open AccessReview

Overview of Cancer Metabolism and Signaling Transduction

by Hee-Suk Chae and Seong-Tshool Hong

Int. J. Mol. Sci. 2023, 24(1), 12; https://doi.org/10.3390/ijms24010012 - 20 Dec 2022

Cited by 26 | Viewed by 4237

Abstract

Despite the remarkable progress in cancer treatment up to now, we are still far from conquering the disease. The most substantial change after the malignant transformation of normal cells into cancer cells is the alteration in their metabolism. Cancer cells reprogram their metabolism to support the elevated energy demand as well as the acquisition and maintenance of their malignancy, even in nutrient-poor environments. The metabolic alterations, even under aerobic conditions, such as the upregulation of the glucose uptake and glycolysis (the Warburg effect), increase the ROS (reactive oxygen species) and glutamine dependence, which are the prominent features of cancer metabolism. Among these metabolic alterations, high glutamine dependency has attracted serious attention in the cancer research community. In addition, the oncogenic signaling pathways of the well-known important genetic mutations play important regulatory roles, either directly or indirectly, in the central carbon metabolism. The identification of the convergent metabolic phenotypes is crucial to the targeting of cancer cells. In this review, we investigate the relationship between cancer metabolism and the signal transduction pathways, and we highlight the recent developments in anti-cancer therapy that target metabolism. Full article

(This article belongs to the Special Issue Signaling Transduction in Cancer Metabolism)

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18 pages, 755 KiB

Open AccessReview

The Involvement of Long Non-Coding RNAs in Glutamine-Metabolic Reprogramming and Therapeutic Resistance in Cancer

by Jungwook Roh, Mijung Im, Yeonsoo Chae, JiHoon Kang and Wanyeon Kim

Int. J. Mol. Sci. 2022, 23(23), 14808; https://doi.org/10.3390/ijms232314808 - 26 Nov 2022

Cited by 6 | Viewed by 2423

Abstract

Metabolic alterations that support the supply of biosynthetic molecules necessary for rapid and sustained proliferation are characteristic of cancer. Some cancer cells rely on glutamine to maintain their energy requirements for growth. Glutamine is an important metabolite in cells because it not only links to the tricarboxylic acid cycle by producing α-ketoglutarate by glutaminase and glutamate dehydrogenase but also supplies other non-essential amino acids, fatty acids, and components of nucleotide synthesis. Altered glutamine metabolism is associated with cancer cell survival, proliferation, metastasis, and aggression. Furthermore, altered glutamine metabolism is known to be involved in therapeutic resistance. In recent studies, lncRNAs were shown to act on amino acid transporters and glutamine-metabolic enzymes, resulting in the regulation of glutamine metabolism. The lncRNAs involved in the expression of the transporters include the abhydrolase domain containing 11 antisense RNA 1, LINC00857, plasmacytoma variant translocation 1, Myc-induced long non-coding RNA, and opa interacting protein 5 antisense RNA 1, all of which play oncogenic roles. When it comes to the regulation of glutamine-metabolic enzymes, several lncRNAs, including nuclear paraspeckle assembly transcript 1, XLOC_006390, urothelial cancer associated 1, and thymopoietin antisense RNA 1, show oncogenic activities, and others such as antisense lncRNA of glutaminase, lincRNA-p21, and ataxin 8 opposite strand serve as tumor suppressors. In addition, glutamine-dependent cancer cells with lncRNA dysregulation promote cell survival, proliferation, and metastasis by increasing chemo- and radio-resistance. Therefore, understanding the roles of lncRNAs in glutamine metabolism will be helpful for the establishment of therapeutic strategies for glutamine-dependent cancer patients. Full article

(This article belongs to the Special Issue Signaling Transduction in Cancer Metabolism)

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13 pages, 1103 KiB

Open AccessReview

Targeting Oncogenic Rewiring of Lipid Metabolism for Glioblastoma Treatment

by Haksoo Lee, Dahye Kim and BuHyun Youn

Int. J. Mol. Sci. 2022, 23(22), 13818; https://doi.org/10.3390/ijms232213818 - 10 Nov 2022

Cited by 10 | Viewed by 3056

Abstract

Glioblastoma (GBM) is the most malignant primary brain tumor. Despite increasing research on GBM treatment, the overall survival rate has not significantly improved over the last two decades. Although recent studies have focused on aberrant metabolism in GBM, there have been few advances in clinical application. Thus, it is important to understand the systemic metabolism to eradicate GBM. Together with the Warburg effect, lipid metabolism has emerged as necessary for GBM progression. GBM cells utilize lipid metabolism to acquire energy, membrane components, and signaling molecules for proliferation, survival, and response to the tumor microenvironment. In this review, we discuss fundamental cholesterol, fatty acid, and sphingolipid metabolism in the brain and the distinct metabolic alterations in GBM. In addition, we summarize various studies on the regulation of factors involved in lipid metabolism in GBM therapy. Focusing on the rewiring of lipid metabolism will be an alternative and effective therapeutic strategy for GBM treatment. Full article

(This article belongs to the Special Issue Signaling Transduction in Cancer Metabolism)

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18 pages, 1701 KiB

Open AccessReview

The Role of IL-7 and IL-7R in Cancer Pathophysiology and Immunotherapy

by Chunli Wang, Lingzu Kong, Seokmin Kim, Sunyoung Lee, Sechan Oh, Seona Jo, Inhwan Jang and Tae-Don Kim

Int. J. Mol. Sci. 2022, 23(18), 10412; https://doi.org/10.3390/ijms231810412 - 8 Sep 2022

Cited by 41 | Viewed by 7346

Abstract

Interleukin-7 (IL-7) is a multipotent cytokine that maintains the homeostasis of the immune system. IL-7 plays a vital role in T-cell development, proliferation, and differentiation, as well as in B cell maturation through the activation of the IL-7 receptor (IL-7R). IL-7 is closely associated with tumor development and has been used in cancer clinical research and therapy. In this review, we first summarize the roles of IL-7 and IL-7Rα and their downstream signaling pathways in immunity and cancer. Furthermore, we summarize and discuss the recent advances in the use of IL-7 and IL-7Rα as cancer immunotherapy tools and highlight their potential for therapeutic applications. This review will help in the development of cancer immunotherapy regimens based on IL-7 and IL-7Rα, and will also advance their exploitation as more effective and safe immunotherapy tools. Full article

(This article belongs to the Special Issue Signaling Transduction in Cancer Metabolism)

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