The Implications of PDK1–4 on Tumor Energy Metabolism, Aggressiveness and Therapy Resistance DOI Creative Commons

Emine Atas,

Monika Oberhuber, Lukas Kenner

et al.

Frontiers in Oncology, Journal Year: 2020, Volume and Issue: 10

Published: Dec. 15, 2020

A metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis—known as the Warburg effect—is characteristic for many cancers. It gives cancer cells a survival advantage in hypoxic tumor microenvironment and protects them cytotoxic effects of damage apoptosis. The main regulators this are pyruvate dehydrogenase complex kinase (PDK) isoforms 1–4. PDK is known be overexpressed several cancers associated with bad prognosis therapy resistance. Whereas expression PDK1–3 tissue specific, PDK4 dependent on energetic state whole organism. In contrast other isoforms, not only oncogenic, but also suppressive functions have been reported. tumors that profit high OXPHOS de novo fatty acid synthesis, can protective effect. This case prostate cancer, most common men, makes an interesting therapeutic target. While work focused characterized by glycolytic activity, little research devoted those cases where acts therefore highly needed.

Language: Английский

NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy resistance DOI Creative Commons
Tingjin Chen, Zhigang Xu,

Jie Luo

et al.

Cell Metabolism, Journal Year: 2023, Volume and Issue: 35(10), P. 1782 - 1798.e8

Published: Aug. 15, 2023

Language: Английский

Citations

84
Kaempferol Can Reverse the 5-Fu Resistance of Colorectal Cancer Cells by Inhibiting PKM2-Mediated Glycolysis DOI Open Access
Haili Wu,

Jin’e Du,

Chenglu Li

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(7), P. 3544 - 3544

Published: March 24, 2022

Resistance to 5-Fluorouracil (5-Fu) chemotherapy is the main cause of treatment failure in cure colon cancer. Therefore, there an urgent need explore a safe and effective multidrug resistance reversal agent for colorectal cancer, which would be great significance improving clinical efficacy. The dietary flavonoid kaempferol plays key role progression cancer 5-Fu resistance. However, molecular mechanism reversing human cells still unclear. We found that could reverse drug HCT8-R 5-Fu, suggesting alone or combination with has potential treat It well known aerobic glycolysis related tumor growth Indeed, significantly reduced glucose uptake lactic acid production drug-resistant cells. In terms mechanism, promotes expression microRNA-326 (miR-326) cells, miR-326 inhibit process by directly targeting pyruvate kinase M2 isoform (PKM2) 3'-UTR (untranslated region) PKM2 indirectly block alternative splicing factors PKM mRNA, then 5-Fu. Taken together, our data suggest may play important overcoming therapy regulating miR-326-hnRNPA1/A2/PTBP1-PKM2 axis.

Language: Английский

Citations

76
NEK2 Promotes Aerobic Glycolysis in Multiple Myeloma Through Regulating Splicing of Pyruvate Kinase DOI Creative Commons
Zhimin Gu, Jiliang Xia, Hongwei Xu

et al.

Journal of Hematology & Oncology, Journal Year: 2017, Volume and Issue: 10(1)

Published: Jan. 13, 2017

Aerobic glycolysis, a hallmark of cancer, is characterized by increased metabolism glucose and production lactate in normaxia. Recently, pyruvate kinase M2 (PKM2) has been identified as key player for regulating aerobic glycolysis promoting tumor cell proliferation survival. Tandem affinity purification followed up mass spectrometry (TAP-MS) co-immunoprecipitation (Co-IP) were used to study the interaction between NIMA (never mitosis gene A)-related 2 (NEK2) heterogeneous nuclear ribonucleoproteins (hnRNP) A1/2. RNA immunoprecipitation (RIP) was performed identify NEK2 binding PKM pre-mRNA sequence. Chromatin-immunoprecipitation (ChIP)-PCR analyze transcriptional regulation c-Myc. Western blot real-time PCR executed PKM2 NEK2. regulates alternative splicing immature multiple myeloma cells interacting with hnRNPA1/2. RIP shows that binds intronic sequence flanking exon 9 pre-mRNA. Knockdown decreases ratio PKM2/PKM1 also other genes including GLUT4, HK2, ENO1, LDHA, MCT4. Myeloma patients high expression have lower event-free survival overall Our data indicate transcriptionally regulated c-Myc cells. Ectopic partially rescues growth inhibition death induced silenced studies demonstrate promotes through increasing which contributes its oncogenic activity.

Language: Английский

Citations

123
Enolase 1 stimulates glycolysis to promote chemoresistance in gastric cancer DOI Open Access

Xiaoling Qian,

Wenxia Xu,

Jinye Xu

et al.

Oncotarget, Journal Year: 2017, Volume and Issue: 8(29), P. 47691 - 47708

Published: May 15, 2017

Chemotherapy is the major choice for cancer treatment of early and advanced stages. However, intrinsic or acquired drug resistance significantly restricts clinical efficacy chemotherapy. It critical to develop novel approaches detect overcome resistance. In this study, we demonstrated that accelerated glycolysis played a pivotal role in both cisplatin-resistance gastric cells. The metabolic reprogramming cisplatin-resistant cells was characterized by increased dependence. Inhibition with glucose starvation 2-Deoxy-D-glucose (2-DG) reversed By proteomic screening, found expression glycolytic enzyme Enolase 1 (ENO1) Depletion ENO1 siRNA reduced Moreover, attributed down-regulation ENO1-targeting miR-22, rather than activated gene transcriptional prolonged protein stability. Finally, elevated levels proteins were associated shorter overall survival patients. conclusion, biomarker predict prognosis cancer. Targeting chemical inhibitors up-regulating miR-22 could be valuable

Language: Английский

Citations

121
A widespread role for SLC transmembrane transporters in resistance to cytotoxic drugs DOI
Enrico Girardi, Adrián César‐Razquin, Sabrina Lindinger

et al.

Nature Chemical Biology, Journal Year: 2020, Volume and Issue: 16(4), P. 469 - 478

Published: March 9, 2020

Language: Английский

Citations

116
Non-proteolytic ubiquitination of Hexokinase 2 by HectH9 controls tumor metabolism and cancer stem cell expansion DOI Creative Commons

Hong‐Jen Lee,

Chien‐Feng Li,

Diane Ruan

et al.

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: June 14, 2019

Abstract Enormous efforts have been made to target metabolic dependencies of cancer cells for developing new therapies. However, the therapeutic efficacy glycolysis inhibitors is limited due their inability elicit cell death. Hexokinase 2 (HK2), via its mitochondrial localization, functions as a central nexus integrating activation and apoptosis resilience. Here we identify that K63-linked ubiquitination by HectH9 regulates localization function HK2. Through stable isotope tracer approach functional analyses, show deficiency impedes tumor glucose metabolism growth HK2 inhibition. The HectH9/HK2 pathway stem (CSC) expansion CSC-associated chemoresistance. Histological analyses expression upregulated correlated with disease progression in prostate cancer. This work uncovers novel regulator metabolism. Targeting represents an effective strategy achieve long-term remission concomitantly disrupting inducing apoptosis.

Language: Английский

Citations

110
A new mechanism of trastuzumab resistance in gastric cancer: MACC1 promotes the Warburg effect via activation of the PI3K/AKT signaling pathway DOI Creative Commons
Jing Liu,

Changqie Pan,

Lihong Guo

et al.

Journal of Hematology & Oncology, Journal Year: 2016, Volume and Issue: 9(1)

Published: Aug. 31, 2016

Trastuzumab, a humanized antibody targeting HER2, exhibits remarkable therapeutic efficacy against HER2-positive gastric cancer. However, recurrent resistance presents revolutionary claims. Warburg effect and AKT signaling pathway was involved in the to trastuzumab. Our previous studies have demonstrated that overexpression of metastasis associated with colon cancer 1 (MACC1) predicted poor prognosis GC promoted tumor cells proliferation invasion. In this study, we found MACC1 significantly upregulated trastuzumab-resistant cell lines. Besides, downregulation reversed resistance.The trastuzumab glycolysis inhibitor combination on viability, apoptosis, metabolism investigated vitro using established We assessed impact combined oxamate growth an xenograft model lines.Here, resistance. Overexpression MACC1-induced resistance, enhanced effect, activated PI3K/AKT pathway, while presented opposite effects. Moreover, when inhibited, effects were diminished. findings indicated mainly through which further resistance.Our results indicate co-targeting HER2 vivo, suggesting might overcome MACC1-overexpressed, patients.

Language: Английский

Citations

108
Berberine Enhances Chemosensitivity and Induces Apoptosis Through Dose-orchestrated AMPK Signaling in Breast Cancer DOI Creative Commons
Yue Pan, Fan Zhang,

Yawei Zhao

et al.

Journal of Cancer, Journal Year: 2017, Volume and Issue: 8(9), P. 1679 - 1689

Published: Jan. 1, 2017

Breast cancer is the most common malignancy in women. Although personalized or targeting molecular therapy more popular up to now, cytotoxicity chemotherapy for patients with advanced breast considered as alternative option. However, chemoresistance still and critical limitation treatment. Berberine, known AMPK activator, has shown multiple activities including antitumor effect. In this study, we investigate chemosensitive effect of different dosages berberine on drug-resistant human MCF-7/MDR cell vitro vivo, mechanisms underlying activation Doxorubicin (DOX) chemosensitivity. Our results showed that could overcome DOX resistance dose-orchestrated manner: On one hand, low-dose can enhance sensitivity drug-resistance cells through AMPK-HIF-1α-P-gp pathway. other high-dose alone directly induces apoptosis AMPK-p53 pathway independence HIF-1α expression. Taken together, our findings demonstrate sensitizes signaling vivo. Berberine appears be a promising chemosensitizer chemotherapeutic drug

Language: Английский

Citations

105
Metabolic reprogramming in the tumour microenvironment: a hallmark shared by cancer cells and T lymphocytes DOI Open Access

Katrina E. Allison,

Brenda L. Coomber, Byram W. Bridle

et al.

Immunology, Journal Year: 2017, Volume and Issue: 152(2), P. 175 - 184

Published: June 16, 2017

Summary Altered metabolism is a hallmark of cancers, including shifting oxidative phosphorylation to glycolysis and up‐regulating glutaminolysis divert carbon sources into biosynthetic pathways that promote proliferation survival. Therefore, metabolic inhibitors represent promising anti‐cancer drugs. However, T cells must rapidly divide survive in harsh microenvironments mediate effects. Metabolic profiles cancer activated lymphocytes are similar, raising the risk impairing immune system. Immune checkpoint blockade provides an example how can be differentially impacted impair but support cells. Implications for research with discussed.

Language: Английский

Citations

99
USP22 mediates the multidrug resistance of hepatocellular carcinoma via the SIRT1/AKT/MRP1 signaling pathway DOI Creative Commons
Sunbin Ling, Jie Li,

Qiaonan Shan

et al.

Molecular Oncology, Journal Year: 2017, Volume and Issue: 11(6), P. 682 - 695

Published: April 18, 2017

Drug treatments for hepatocellular carcinoma (HCC) often fail because of multidrug resistance (MDR). The mechanisms MDR are complex but cancer stem cells (CSCs), which able to self-renew and differentiate, have recently been shown be involved. deubiquitinating enzyme ubiquitin-specific protease 22 (USP22) is a marker CSCs. This study aimed elucidate the role USP22 in HCC underlying mechanisms. Using vitro vivo assays, we found that modified levels were responsible altered drug-resistant phenotype BEL7402 BEL/FU cells. Downregulation dramatically inhibited expression ABCC1 (encoding MRP1) weakly influenced ABCB1 P-glycoprotein). Sirtuin 1 (SIRT1) was reported previously as functional mediator could promote cell proliferation enhance chemotherapy. In this study, directly interacted with SIRT1 positively regulated protein expression. Regulation both markedly affected AKT pathway MRP1 Inhibition by its specific inhibitor LY294002 resulted downregulation MRP1. detected 168 clinical samples immunohistochemical staining, firm relationship between identified. Together, these results indicate activating SIRT1/AKT/MRP1 pathway. might potential target, through setting reversed.

Language: Английский

Citations

96