Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer

Although the addition of the prosthetic group lipoate is essential to the activity of critical mitochondrial catabolic enzymes, its regulation is unknown. Here, we show that lipoylation of the pyruvate dehydrogenase and α-ketoglutarate dehydrogenase (αKDH) complexes is a dynamically regulated process that is inhibited under hypoxia and in cancer cells to restrain mitochondrial respiration. Mechanistically, we found that the polymerase-δ interacting protein 2 (Poldip2), a nuclear-encoded mitochondrial protein of unknown function, controls the lipoylation of the pyruvate and α-KDH dihydrolipoamide acetyltransferase subunits by a mechanism that involves regulation of the caseinolytic peptidase (Clp)-protease complex and degradation of the lipoate-activating enzyme Ac-CoA synthetase medium-chain family member 1 (ACSM1). ACSM1 is required for the utilization of lipoic acid derived from a salvage pathway, an unacknowledged lipoylation mechanism. In Poldip2-deficient cells, reduced lipoylation represses mitochondrial function and induces the stabilization of hypoxia-inducible factor 1α (HIF-1α) by loss of substrate inhibition of prolyl-4-hydroxylases (PHDs). HIF-1α–mediated retrograde signaling results in a metabolic reprogramming that resembles hypoxic and cancer cell adaptation. Indeed, we observe that Poldip2 expression is down-regulated by hypoxia in a variety of cell types and basally repressed in triple-negative cancer cells, leading to inhibition of lipoylation of the pyruvate and α-KDH complexes and mitochondrial dysfunction. Increasing mitochondrial lipoylation by forced expression of Poldip2 increases respiration and reduces the growth rate of cancer cells. Our work unveils a regulatory mechanism of catabolic enzymes required for metabolic plasticity and highlights the role of Poldip2 as key during hypoxia and cancer cell metabolic adaptation.

Download Full-text

SIRT7–SREBP1 restrains cancer cell metabolic reprogramming by upregulating IDH1

Genome Instability & Disease ◽

10.1007/s42764-021-00031-4 ◽

2021 ◽

Author(s):

Fengting Su ◽

Xiaolong Tang ◽

Guo Li ◽

Andreas Koeberle ◽

Baohua Liu

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Therapeutic Intervention ◽

Warburg Effect ◽

Lung Metastases ◽

Cell Types ◽

Metabolic Reprogramming ◽

Protein Levels ◽

Underlying Mechanisms

AbstractSIRT7 plays critical roles in tumorigenesis and tumor progression; however, the underlying mechanisms are poorly understood. Here, we aimed to identify downstream targets of SIRT7 to help delineate its precise function. In this study, we demonstrate that SIRT7 is essential to regulate IDH1 expression in various cancer cell types. Interestingly, both SIRT7 and IDH1 levels are downregulated in breast cancer lung metastases and are useful for predicting disease progression and prognosis. Mechanistically, SIRT7 enhances IDH1 transcription, and this process is mediated by SREBP1. SIRT7 insufficiency reduces cellular α-ketoglutarate, a metabolite product of IDH1, and suppresses lipogenesis and gluconeogenesis. Moreover, α-ketoglutarate decline increases HIF1α protein levels and, thus, promotes glycolysis. This effect permits cancer cells to facilitate Warburg effect and undergo fast proliferation. Overall, the SIRT7–IDH1 axis regulates cancer cell metabolic reprogramming and, thus, might serve as a point of therapeutic intervention.

Download Full-text

The metabolic adaptation mechanism of metastatic organotropism

Experimental Hematology and Oncology ◽

10.1186/s40164-021-00223-4 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Chao Wang ◽

Daya Luo

Keyword(s):

Cancer Cells ◽

Cancer Cell ◽

Cancer Progression ◽

Cancer Metabolism ◽

Cancer Metastasis ◽

Tumour Microenvironment ◽

Metabolic Adaptation ◽

Adaptation Mechanism ◽

Metastatic Sites ◽

The Impact

AbstractMetastasis is a complex multistep cascade of cancer cell extravasation and invasion, in which metabolism plays an important role. Recently, a metabolic adaptation mechanism of cancer metastasis has been proposed as an emerging model of the interaction between cancer cells and the host microenvironment, revealing a deep and extensive relationship between cancer metabolism and cancer metastasis. However, research on how the host microenvironment affects cancer metabolism is mostly limited to the impact of the local tumour microenvironment at the primary site. There are few studies on how differences between the primary and secondary microenvironments promote metabolic changes during cancer progression or how secondary microenvironments affect cancer cell metastasis preference. Hence, we discuss how cancer cells adapt to and colonize in the metabolic microenvironments of different metastatic sites to establish a metastatic organotropism phenotype. The mechanism is expected to accelerate the research of cancer metabolism in the secondary microenvironment, and provides theoretical support for the generation of innovative therapeutic targets for clinical metastatic diseases.

Download Full-text

Selective Effects of Thioridazine on Self-Renewal of Basal-Like Breast Cancer Cells

Scientific Reports ◽

10.1038/s41598-019-55145-3 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Matthew Tegowski ◽

Cheng Fan ◽

Albert S. Baldwin

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Breast Cancer Cells ◽

Cell Types ◽

Breast Cancer Cell Lines ◽

Breast Cancers ◽

Self Renewal ◽

Basal Like Breast Cancer

AbstractSeveral recent publications demonstrated that DRD2-targeting antipsychotics such as thioridazine induce proliferation arrest and apoptosis in diverse cancer cell types including those derived from brain, lung, colon, and breast. While most studies show that 10–20 µM thioridazine leads to reduced proliferation or increased apoptosis, here we show that lower doses of thioridazine (1–2 µM) target the self-renewal of basal-like breast cancer cells, but not breast cancer cells of other subtypes. We also show that all breast cancer cell lines tested express DRD2 mRNA and protein, regardless of thioridazine sensitivity. Further, DRD2 stimulation with quinpirole, a DRD2 agonist, promotes self-renewal, even in cell lines in which thioridazine does not inhibit self-renewal. This suggests that DRD2 is capable of promoting self-renewal in these cell lines, but that it is not active. Further, we show that dopamine can be detected in human and mouse breast tumor samples. This observation suggests that dopamine receptors may be activated in breast cancers, and is the first time to our knowledge that dopamine has been directly detected in human breast tumors, which could inform future investigation into DRD2 as a therapeutic target for breast cancer.

Download Full-text

Alternative Pathways of Cancer Cell Death by Rottlerin: Apoptosis versus Autophagy

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/980658 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 17

Author(s):

Claudia Torricelli ◽

Sara Salvadori ◽

Giuseppe Valacchi ◽

Karel Souček ◽

Eva Slabáková ◽

...

Keyword(s):

Cell Death ◽

Cancer Cells ◽

Cancer Cell ◽

Electron Microscopic Examination ◽

Cell Types ◽

Beclin 1 ◽

Electron Microscopic ◽

Alternative Pathways ◽

Light Fluorescence ◽

Mcf 7

Since the ability of cancer cells to evade apoptosis often limits the efficacy of radiotherapy and chemotherapy, autophagy is emerging as an alternative target to promote cell death. Therefore, we wondered whether Rottlerin, a natural polyphenolic compound with antiproliferative effects in several cell types, can induce cell death in MCF-7 breast cancer cells. The MCF-7 cell line is a good model of chemo/radio resistance, being both apoptosis and autophagy resistant, due to deletion of caspase 3 gene, high expression of the antiapoptotic protein Bcl-2, and low expression of the autophagic Beclin-1 protein. The contribution of autophagy and apoptosis to the cytotoxic effects of Rottlerin was examined by light, fluorescence, and electron microscopic examination and by western blotting analysis of apoptotic and autophagic markers. By comparing caspases-3-deficient (MCF-73def) and caspases-3-transfected MCF-7 cells (MCF-73trans), we found that Rottlerin induced a noncanonical, Bcl-2-, Beclin 1-, Akt-, and ERK-independent autophagic death in the former- and the caspases-mediated apoptosis in the latter, in not starved conditions and in the absence of any other treatment. These findings suggest that Rottlerin could be cytotoxic for different cancer cell types, both apoptosis competent and apoptosis resistant.

Download Full-text

ANKRD22, a novel tumor microenvironment-induced mitochondrial protein promotes metabolic reprogramming of colorectal cancer cells

Theranostics ◽

10.7150/thno.37472 ◽

2020 ◽

Vol 10 (2) ◽

pp. 516-536

Author(s):

Tianhui Pan ◽

Jingwen Liu ◽

Song Xu ◽

Qiao Yu ◽

Hongping Wang ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Microenvironment ◽

Cancer Cells ◽

Mitochondrial Protein ◽

Metabolic Reprogramming ◽

Colorectal Cancer Cells

Download Full-text

A combined computational pipeline to detect circular RNAs in human cancer cells under hypoxic stress

Journal of Molecular Cell Biology ◽

10.1093/jmcb/mjz094 ◽

2019 ◽

Vol 11 (10) ◽

pp. 829-844 ◽

Cited By ~ 5

Author(s):

Antonella Di Liddo ◽

Camila de Oliveira Freitas Machado ◽

Sandra Fischer ◽

Stefanie Ebersberger ◽

Andreas W Heumüller ◽

...

Keyword(s):

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Human Cancer ◽

Cancer Cell Lines ◽

Metabolic Adaptation ◽

Circular Rnas ◽

Hypoxic Stress ◽

Computational Pipeline ◽

Transcriptional Responses

Abstract Hypoxia is associated with several diseases, including cancer. Cells that are deprived of adequate oxygen supply trigger transcriptional and post-transcriptional responses, which control cellular pathways such as angiogenesis, proliferation, and metabolic adaptation. Circular RNAs (circRNAs) are a novel class of mainly non-coding RNAs, which have been implicated in multiple cancers and attract increasing attention as potential biomarkers. Here, we characterize the circRNA signatures of three different cancer cell lines from cervical (HeLa), breast (MCF-7), and lung (A549) cancer under hypoxia. In order to reliably detect circRNAs, we integrate available tools with custom approaches for quantification and statistical analysis. Using this consolidated computational pipeline, we identify ~12000 circRNAs in the three cancer cell lines. Their molecular characteristics point to an involvement of complementary RNA sequences as well as trans-acting factors in circRNA biogenesis, such as the RNA-binding protein HNRNPC. Notably, we detect a number of circRNAs that are more abundant than their linear counterparts. In addition, 64 circRNAs significantly change in abundance upon hypoxia, in most cases in a cell type-specific manner. In summary, we present a comparative circRNA profiling in human cancer cell lines, which promises novel insights into the biogenesis and function of circRNAs under hypoxic stress.

Download Full-text

Superoxide Dismutase 1 Regulation of CXCR4-Mediated Signaling in Prostate Cancer Cells is Dependent on Cellular Oxidative State

Cellular Physiology and Biochemistry ◽

10.1159/000438566 ◽

2015 ◽

Vol 37 (6) ◽

pp. 2071-2084 ◽

Cited By ~ 6

Author(s):

Brent Young ◽

Chad Purcell ◽

Yi-Qun Kuang ◽

Nicholle Charette ◽

Denis J. Dupré

Keyword(s):

Prostate Cancer ◽

Superoxide Dismutase ◽

Cancer Cells ◽

Cancer Cell ◽

Cancer Metastasis ◽

Direct Interaction ◽

Cancer Cell Line ◽

Prostate Cancer Cell Line ◽

Cell Types ◽

Intracellular Loop

Background/Aims: CXCL12, acting via one of its G protein-coupled receptors, CXCR4, is a chemoattractant for a broad range of cell types, including several types of cancer cells. Elevated expression of CXCR4, and its ligand CXCL12, play important roles in promoting cancer metastasis. Cancer cells have the potential for rapid and unlimited growth in an area that may have restricted blood supply, as oxidative stress is a common feature of solid tumors. Recent studies have reported that enhanced expression of cytosolic superoxide dismutase (SOD1), a critical enzyme responsible for regulation of superoxide radicals, may increase the aggressive and invasive potential of malignant cells in some cancers. Methods: We used a variety of biochemical approaches and a prostate cancer cell line to study the effects of SOD1 on CXCR4 signaling. Results: Here, we report a direct interaction between SOD1 and CXCR4. We showed that SOD1 interacts directly with the first intracellular loop (ICL1) of CXCR4 and that the CXCL12/CXCR4-mediated regulation of AKT activation, apoptosis and cell migration in prostate cancer (PCa) cells is differentially modulated under normal versus hypoxic conditions when SOD1 is present. Conclusions: This study highlights a potential new regulatory mechanism by which a sensor of the oxidative environment could directly regulate signal transduction of a receptor involved in cancer cell survival and migration.

Download Full-text

Microarray analysis reveals ONC201 mediated differential mechanisms of CHOP gene regulation in metastatic and nonmetastatic colorectal cancer cells

Scientific Reports ◽

10.1038/s41598-021-91092-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ashraf Al Madhoun ◽

Dania Haddad ◽

Mustafa Al Tarrah ◽

Sindhu Jacob ◽

Waleed Al-Ali ◽

...

Keyword(s):

Cell Lines ◽

Cancer Cell ◽

Rna Splicing ◽

Metastatic Cancer ◽

Cell Types ◽

Metabolic Reprogramming ◽

Homologous Protein ◽

Chop Expression ◽

Colorectal Cell ◽

Cellular Responsiveness

AbstractThe imipramine ONC201 has antiproliferative effects in several cancer cell types and activates integrated stress response pathway associated with the induction of Damage Inducible Transcript 3 (DDIT3, also known as C/EBP homologous protein or CHOP). We investigated the signaling pathways through which ONC201/CHOP crosstalk is regulated in ONC201-treated nonmetastatic and metastatic cancer cell lines (Dukes' type B colorectal adenocarcinoma nonmetastatic SW480 and metastatic LS-174T cells, respectively). Cell proliferation and apoptosis were evaluated by MTT assays and flow cytometry, gene expression was assessed by Affymetrix microarray, signaling pathway perturbations were assessed in silico, and key regulatory proteins were validated by Western blotting. Unlike LS-174T cells, SW480 cells were resistant to ONC201 treatment; Gene Ontology analysis of differentially expressed genes showed that cellular responsiveness to ONC201 treatment also differed substantially. In both ONC201-treated cell lines, CHOP expression was upregulated; however, its upstream regulatory mechanisms were perturbed. Although, PERK, ATF6 and IRE1 ER-stress pathways upregulated CHOP in both cell types, the Bak/Bax pathway regulated CHOP only LS-174T cells. Additionally, CHOP RNA splicing profiles varied between cell lines; these were further modified by ONC201 treatment. In conclusion, we delineated the signaling mechanisms by which CHOP expression is regulated in ONC201-treated non-metastatic and metastatic colorectal cell lines. The observed differences could be related to cellular plasticity and metabolic reprogramming, nevertheless, detailed mechanistic studies are required for further validations.

Download Full-text

Metabolic Heterogeneity of Cancer Cells: An Interplay between Reprogrammed and Oxidative Metabolism and Roles of HIF-1, GLUTs and AMPK

10.20944/preprints202002.0436.v1 ◽

2020 ◽

Author(s):

Nurbubu T. Moldogazieva ◽

Innokenty M. Mokhosoev ◽

Alexander A. Terentiev

Keyword(s):

Cancer Cells ◽

Cancer Cell ◽

Oxidative Metabolism ◽

Cell Metabolism ◽

Hypoxia Inducible Factor ◽

Metabolic Plasticity ◽

Anti Cancer ◽

Cancer Cell Metabolism ◽

Metabolic Heterogeneity ◽

Amp Activated Protein Kinase

It has been long recognized that under hypoxia conditions cancer cells reprogram their metabolism through shift from oxidative phosphorylation (OXPHOS) to glycolysis to meet elevated requirements in energy and nutrients for proliferation, migration and survival. However, data accumulated over the last years increasingly evidence that cancer cells can revert from glycolysis to OXPHOS and maintain both reprogrammed and oxidative metabolism even in the same tumor. The phenomenon denoted as cancer cell metabolic plasticity or hybrid metabolism depends on a tumor micro-environment, which is highly heterogeneous and influenced by intensity of vasculature and blood flow, oxygen concentration, nutrient and energy supply, and requires regulatory interplay between multiple oncogenes, transcription factors, growth factors, reactive oxygen species (ROS), etc. Hypoxia-inducible factor-1 (HIF-1) and AMP-activated protein kinase (AMPK) represent key modulators of switch between reprogrammed and oxidative metabolism. The present review focuses on cross-talks between HIF-1, GLUTs, and AMPK and other regulatory proteins including oncogenes such as c-Myc, p53 and KRAS, growth factor-initiated PKB/Akt, PI3K and mTOR signaling pathways and tumor suppressors such as LKB1 and TSC1 in controlling cancer cell metabolism. The multiple switches between metabolic pathways can underlie chemo-resistance to conventional anti-cancer therapy and should be taken into account in choosing molecular targets to discovery novel anti-cancer drugs.

Download Full-text

The landscape of metabolic pathway dependencies in cancer cell lines

PLoS Computational Biology ◽

10.1371/journal.pcbi.1008942 ◽

2021 ◽

Vol 17 (4) ◽

pp. e1008942

Author(s):

James H. Joly ◽

Brandon T. L. Chew ◽

Nicholas A. Graham

Keyword(s):

Cell Culture ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Metabolic Pathway ◽

Culture Medium ◽

Cancer Cell Lines ◽

Metabolic Reprogramming ◽

Cell Culture Medium ◽

Loss Of Function

The metabolic reprogramming of cancer cells creates metabolic vulnerabilities that can be therapeutically targeted. However, our understanding of metabolic dependencies and the pathway crosstalk that creates these vulnerabilities in cancer cells remains incomplete. Here, by integrating gene expression data with genetic loss-of-function and pharmacological screening data from hundreds of cancer cell lines, we identified metabolic vulnerabilities at the level of pathways rather than individual genes. This approach revealed that metabolic pathway dependencies are highly context-specific such that cancer cells are vulnerable to inhibition of one metabolic pathway only when activity of another metabolic pathway is altered. Notably, we also found that the no single metabolic pathway was universally essential, suggesting that cancer cells are not invariably dependent on any metabolic pathway. In addition, we confirmed that cell culture medium is a major confounding factor for the analysis of metabolic pathway vulnerabilities. Nevertheless, we found robust associations between metabolic pathway activity and sensitivity to clinically approved drugs that were independent of cell culture medium. Lastly, we used parallel integration of pharmacological and genetic dependency data to confidently identify metabolic pathway vulnerabilities. Taken together, this study serves as a comprehensive characterization of the landscape of metabolic pathway vulnerabilities in cancer cell lines.

Download Full-text