Optogenetic screening of MCT1 activity implicates a cluster of non-steroidal anti-inflammatory drugs (NSAIDs) as inhibitors of lactate transport DOI Creative Commons

Scott A. Wegner,

Hahn Kim, José L. Avalos‬

et al.

PLoS ONE, Journal Year: 2024, Volume and Issue: 19(12), P. e0312492 - e0312492

Published: Dec. 12, 2024

Lactate transport plays a crucial role in the metabolism, microenvironment, and survival of cancer cells. However, current drugs targeting either MCT1 or MCT4, which traditionally mediate lactate import efflux respectively, show limited efficacy beyond vitro models. This limitation partly arises from existence both isoforms certain tumors, however existing high-affinity MCT1/4 inhibitors are years away human testing. Therefore, we conducted an optogenetic drug screen Saccharomyces cerevisiae on subset FDA-approved library to identify scaffolds that could be repurposed as monocarboxylate transporter (MCT) inhibitors. Our findings several classes inhibit activity, including non-steroidal estrogens, anti-inflammatory (NSAIDs), natural products (in total representing approximately 1% library, 78 out 6400), with moderate affinity (IC 50 1.8–21 μM). Given well-tolerated nature NSAIDs, their known anticancer properties associated COX inhibition, chose further investigate inhibition profile. The majority NSAIDs our cluster into single large structural grouping. Moreover, this group is predominantly comprised seven exhibiting inhibition. Since these molecules form distinct NSAID MCT4 inhibitors, such diclofenac, ketoprofen, indomethacin, hypothesize newly identified may also transporters. Consequently, class, piroxicam specifically 4.4 μM), demonstrate at theoretically relevant dosages, suggesting immediate potential for standalone MCT combined therapy.

Language: Английский

Exosomal circSIPA1L3-mediated intercellular communication contributes to glucose metabolic reprogramming and progression of triple negative breast cancer DOI Creative Commons
Yiran Liang, Fangzhou Ye, Dan Luo

et al.

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: June 8, 2024

Abstract Background Breast cancer is the most common malignant tumor, and metastasis remains major cause of poor prognosis. Glucose metabolic reprogramming one prominent hallmarks in cancer, providing nutrients energy to support dramatically elevated tumor growth metastasis. Nevertheless, potential mechanistic links between glycolysis breast progression have not been thoroughly elucidated. Methods RNA-seq analysis was used identify glucose metabolism-related circRNAs. The expression circSIPA1L3 tissues serum examined by qRT-PCR, further assessed its diagnostic value. We also evaluated prognostic analyzing a cohort 238 patients. Gain- loss-of-function experiments, transcriptomic analysis, molecular biology experiments were conducted explore biological function regulatory mechanism circSIPA1L3. Results Using identified as critical mediator responsible for adaption upon stress. revealed that exerted stimulative effect on glycolysis, which could be transported exosomes facilitated behaviors among cells. Significantly, lactate secretion caused circSIPA1L3-mediated enhancement promoted recruitment associated macrophage their tumor-promoting roles. Mechanistically, EIF4A3 induced cyclization cytoplasmic export circSIPA1L3, inhibited ubiquitin-mediated IGF2BP3 degradation through enhancing UPS7-IGF2BP3 interaction. Furthermore, increased mRNA stability carrier SLC16A1 intake enhancer RAB11A either strengthening interaction with or sponging miR-665, leading enhanced glycolytic metabolism. Clinically, indicated unfavorable prognosis base Moreover, highly expressed patients exhibited high value Conclusions Our study highlights oncogenic role mediating metabolism, might serve promising biomarker therapeutic target cancer.

Language: Английский

Citations

10
Emerging Role of Extracellular pH in Tumor Microenvironment as a Therapeutic Target for Cancer Immunotherapy DOI Creative Commons
Md. Ataur Rahman,

Mahesh Kumar Yadab,

Meser M. Ali

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(22), P. 1924 - 1924

Published: Nov. 20, 2024

Identifying definitive biomarkers that predict clinical response and resistance to immunotherapy remains a critical challenge. One emerging factor is extracellular acidosis in the tumor microenvironment (TME), which significantly impairs immune cell function contributes failure. However, acidic conditions TME disrupt interaction between cancer cells, driving tumor-infiltrating T cells NK into an inactivated, anergic state. Simultaneously, promotes recruitment activation of immunosuppressive such as myeloid-derived suppressor regulatory (Tregs). Notably, acidity enhances exosome release from Tregs, further amplifying immunosuppression. Tumor thus acts "protective shield," neutralizing anti-tumor responses transforming pro-tumor allies. Therefore, targeting lactate metabolism has emerged promising strategy overcome this barrier, with approaches including buffer agents neutralize pH inhibitors block production or transport, thereby restoring efficacy TME. Recent discoveries have identified genes involved (pHe) regulation, presenting new therapeutic targets. Moreover, ongoing research aims elucidate molecular mechanisms acidification develop treatments modulate levels enhance outcomes. Additionally, future studies are crucial validate safety pHe-targeted therapies patients. Thus, review explores regulation pHe its potential role improving immunotherapy.

Language: Английский

Citations

8
Glycometabolic Reprogramming of Microglia in Neurodegenerative Diseases: Insights from Neuroinflammation DOI Creative Commons
Qi Huang,

Yanfu Wang,

Shanshan Chen

et al.

Aging and Disease, Journal Year: 2023, Volume and Issue: unknown, P. 0 - 0

Published: Jan. 1, 2023

Neurodegenerative diseases (ND) are conditions defined by progressive deterioration of the structure and function nervous system. Some major examples include Alzheimer's disease (AD), Parkinson's (PD), Amyotrophic lateral sclerosis (ALS). These lead to various dysfunctions, like impaired cognition, memory, movement. Chronic neuroinflammation may underlie numerous neurodegenerative disorders. Microglia, an important immunocell in brain, plays a vital role defending against neuroinflammation. When exposed different stimuli, microglia activated assume phenotypes, participating immune regulation system maintaining tissue homeostasis. The immunological activity is affected glucose metabolic alterations. However, context chronic neuroinflammation, specific alterations microglial metabolism their mechanisms action remain unclear. Thus, this paper, we review glycometabolic reprogramming ND. key molecular targets main pathways focus research. Additionally, study explores underlying ND offers analysis most recent therapeutic advancements. ultimate aim provide insights into development potential treatments for

Language: Английский

Citations

15
Research progress on the regulatory role of lactate and lactylation in tumor microenvironment DOI
Chunyan Gao,

Jiali Li,

Baoen Shan

et al.

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2025, Volume and Issue: unknown, P. 189339 - 189339

Published: April 1, 2025

Language: Английский

Citations

0
Hodgkin Lymphoma: A disease shaped by the tumor micro- and macroenvironment DOI

Rebecca Masel,

Megan E. Roche, Ubaldo Martinez‐Outschoorn

et al.

Best Practice & Research Clinical Haematology, Journal Year: 2023, Volume and Issue: 36(4), P. 101514 - 101514

Published: Oct. 7, 2023

Language: Английский

Citations

9
Exploring monocarboxylate transporter inhibition for cancer treatment DOI Creative Commons
Tomas Koltai, Larry Fliegel

Exploration of Targeted Anti-tumor Therapy, Journal Year: 2024, Volume and Issue: 5(1), P. 135 - 169

Published: Feb. 23, 2024

Cells are separated from the environment by a lipid bilayer membrane that is relatively impermeable to solutes. The transport of ions and small molecules across this an essential process in cell biology metabolism. Monocarboxylate transporters (MCTs) belong vast family solute carriers (SLCs) facilitate certain hydrophylic compounds through bilipid membrane. existence 446 genes code for SLCs best evidence their importance. In-depth research on MCTs quite recent probably promoted role cancer development progression. Importantly, it has recently been realized these represent interesting target treatment. search clinically useful monocarboxylate inhibitors even more field. There limited pre-clinical clinical experience with new precise mechanism action still under investigation. What common all them inhibition lactate transport. This review discusses structure function MCTs, participation cancer, old newly developed inhibitors. Some suggestions how improve anticancer effects also discussed.

Language: Английский

Citations

2
Exploring SLC16A1 as an Oncogenic Regulator and Therapeutic Target in Cholangiocarcinoma DOI Creative Commons

Jianxin Huang,

Fahui Liu,

Donghua Liu

et al.

Journal of Cancer, Journal Year: 2024, Volume and Issue: 15(12), P. 3794 - 3808

Published: Jan. 1, 2024

Cholangiocarcinoma (CCA) is a primary malignant tumor of the liver, typically diagnosed in advanced stages.Surgical resection remains principal treatment method clinical practice.Regrettably, majority patients receive their diagnosis at an stage, making surgical intervention unfeasible.While chemotherapy serves as main palliative for CCA, its effectiveness significantly limited due to rapid development chemoresistance.Studying pathogenesis CCA and new resistance targets crucial improving outcomes.In our current study, we first identified expression SLC16A1 transcriptome proteome human tumors found abnormal various cancers.Subsequently, focused attention on role CCA.Utilizing bioinformatics analysis, pioneered identification significance this type cancer.Specifically, higher levels were observed with venous invasion T M stages.Additionally, had poorer prognoses.These results suggest oncogenic CCA.Further immune infiltration analysis revealed significant correlation between cells like neutrophils macrophages microenvironment, indicating SLC16A1's potential involvement regulating microenvironment CCA.Moreover, from functional pathway enrichment analyses that might affect outcomes by participating drug metabolism processes.Finally, through further vitro vivo experiments, confirmed SLC16A1, oncogene promotes growth chemoresistance.Knocking down inhibited enhanced sensitivity 5-Fluorouracil (5-FU).Overall, study reveals key highlights target efficacy sensitivity.

Language: Английский

Citations

2
The role of E3 ubiquitin ligases and deubiquitinases in bladder cancer development and immunotherapy DOI Creative Commons
Xuemei Wang, Ying Zhang, Yao Wu

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: May 5, 2023

Bladder cancer is one of the common malignant urothelial tumors. Post-translational modification (PTMs), including ubiquitination, acetylation, methylation, and phosphorylation, have been revealed to participate in bladder initiation progression. Ubiquitination PTM, which conducted by E1 ubiquitin-activating enzyme, E2 ubiquitin-conjugating enzyme E3 ubiquitin-protein ligase. ubiquitin ligases play a key role oncogenesis progression drug resistance cancer. Therefore, this review, we summarize current knowledge regarding functions development. Moreover, provide evidence regulation immunotherapy Furthermore, mention multiple compounds that target improve therapy efficacy We hope our review can stimulate researchers clinicians investigate whether how targeting acts novel strategy for therapy.

Language: Английский

Citations

6
PD-L1-related IncRNAs are associated with malignant characteristics and immune microenvironment in glioma DOI Creative Commons
Zhiwei Xia, Ruxin Tu, Fangkun Liu

et al.

Aging, Journal Year: 2023, Volume and Issue: 15(19), P. 10785 - 10810

Published: Oct. 12, 2023

The expression of long non-coding RNA (lncRNA) can function as diagnostic and therapeutic biomarker for tumors. This research explores the role PD-L1-related lncRNAs in affecting malignant characteristics immune microenvironment glioma.Downloading gene profiles clinicopathological information glioma from TCGA CGGA databases, 6 were identified through correlation analysis, Cox LASSO regression establishing risk score model based on them. Bioinformatics analysis cell experiments vitro adopted to verify effects LINC01271 glioma.Risk scores (AL355974.3, LINC01271, AC011899.3, MIR4500HG, LINC02594, AL357055.3) reflect immunotherapy response glioma. Patients with high had a worse prognosis, higher abundance M1 subtype macrophages microenvironment, degree tumor malignancy. Experiments confirmed its positive regulatory effect proliferation migration cells.The prognosis independently be used new target evaluation therapy.

Language: Английский

Citations

4
Role of monocarboxylate transporter I/lactate dehydrogenase B-mediated lactate recycling in tamoxifen-resistant breast cancer cells DOI

Min Chang Choi,

Sang Kyum Kim, Young Jae Choi

et al.

Archives of Pharmacal Research, Journal Year: 2023, Volume and Issue: 46(11-12), P. 907 - 923

Published: Dec. 1, 2023

Language: Английский

Citations

4