FOXQ1 promotes pancreatic cancer cell proliferation, tumor stemness, invasion and metastasis through regulation of LDHA-mediated aerobic glycolysis

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(10)

Published: Oct. 24, 2023

Abstract Pancreatic cancer (PC), a gastrointestinal tract malignant tumor, has poor prognosis due to early metastasis and limited response chemotherapy. Therefore, identifying novel therapeutic approaches for PC is critical. Epithelial–mesenchymal transition (EMT) known as the vital progress in development, we constructed EMT-related model screen out that FOXQ1 probably involving EMT regulation. been linked process number of cancers. However, its function unknown. In our work, expression was elevated tissues, high level patients’ prognosis. overexpression promoted aerobic glycolysis enhanced cell proliferation, tumor stemness, invasion, metastasis. Whereas, silencing showed reverse effect. Furthermore, mechanistic studies indicated promotes LDHA transcription, thus modulates enhance by increasing expression. these data suggest may be possible target PC.

Language: Английский

---

Exosomal lncRNA Mir100hg derived from cancer stem cells enhance glycolysis and promote metastasis of lung adenocarcinoma through mircroRNA-15a-5p/31-5p

Cell Communication and Signaling, Journal Year: 2023, Volume and Issue: 21(1)

Published: Sept. 21, 2023

Abstract Background Exosomes are a new class of molecular entities in the metastatic microenvironment, which can mediate bidirectional communication between cells. While exosomes-mediated interactions tumor cells and other cell populations microenvironment have attracted most attention, little is known about significance exosomes mediating interaction non-stemness cancer stem during progression. Methods The structure, sequence downstream target miRNAs lncRNA Mir100hg were predicted by online web resources. bioinformatics prediction results validated with experimental verification: exosome tracing, electron microscopy, Luciferase assay, metabolomics sequencing mouse tail vein model pulmonary metastasis. A complex regulatory network "cancer cells-exosomal lncRNA-non-stem cells" was constructed. Results This study demonstrates firstly that upregulated lung LLC-SD (Lung cells) be delivered to LLC (Lewis via exosomes. In LLC, targets miR-15a-5p miR-31-5p leads increase global glycolytic activity consequently, enhancement their capability. Conclusion We delineated utilized transfer high low-metastatic through exosomal Mir100hg, thereby providing mechanistic insights into two heterogeneous

Language: Английский

---

HERC5 downregulation in non-small cell lung cancer is associated with altered energy metabolism and metastasis

Journal of Experimental & Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 43(1)

Published: April 11, 2024

Metastasis is the leading cause of cancer-related death in non-small cell lung cancer (NSCLC) patients. We previously showed that low HERC5 expression predicts early tumor dissemination and a dismal prognosis NSCLC Here, we performed functional studies to unravel mechanism underlying "metastasis-suppressor" effect HERC5, with focus on mitochondrial metabolism pathways. assessed proliferation, colony formation potential, anchorage-independent growth, migration, wound healing line models overexpression (OE) or knockout (KO). To study dissemination, used these zebrafish experiments intracardial injections nude mice. Mass spectrometry (MS) was analyze protein changes whole-cell extracts. Furthermore, electron microscopy (EM) imaging, cellular respiration, glycolytic activity, lactate production were investigate relationships energy Using different vitro models, cells had increased malignant invasive properties. two vivo xenograft mouse model metastasis (in particular brain). Functional enrichment clustering MS data revealed an increase proteins when levels high. Loss leads Warburg effect, improved adaptation survival under prolonged inhibition oxidative phosphorylation. Taken together, results indicate increases metastatic potential vivo. HERC5-induced proteomic influence pathways, ultimately alterations demonstrating its role as new suppressor gene.

Language: Английский

---

The OGT–c-Myc–PDK2 axis rewires the TCA cycle and promotes colorectal tumor growth

Cell Death and Differentiation, Journal Year: 2024, Volume and Issue: 31(9), P. 1157 - 1169

Published: May 22, 2024

Abstract Deregulated glucose metabolism termed the “Warburg effect” is a fundamental feature of cancers, including colorectal cancer. This typically characterized with an increased rate glycolysis, and concomitant reduced tricarboxylic acid (TCA) cycle as compared to normal cells. How TCA manipulated in cancer cells remains unknown. Here, we show that O -linked N -acetylglucosamine (O-GlcNAc) regulates Depletion OGT, sole transferase O-GlcNAc, significantly increases Mechanistically, OGT-catalyzed O-GlcNAc modification c-Myc at serine 415 (S415) stability, which transcriptionally upregulates expression pyruvate dehydrogenase kinase 2 (PDK2). PDK2 phosphorylates (PDH) inhibit activity mitochondrial complex, reduces metabolism, suppresses reactive oxygen species production, promotes xenograft tumor growth. Furthermore, S415 glycosylation levels positively correlate clinical tissues. study highlights OGT–c-Myc–PDK2 axis key mechanism linking oncoprotein activation deregulated

Language: Английский

---

Acid-adapted cancer cells alkalinize their cytoplasm by degrading the acid-loading membrane transporter anion exchanger 2, SLC4A2

Cell Reports, Journal Year: 2023, Volume and Issue: 42(6), P. 112601 - 112601

Published: June 1, 2023

Acidic environments reduce the intracellular pH (pHi) of most cells to levels that are sub-optimal for growth and cellular functions. Yet, cancers maintain an alkaline cytoplasm despite low extracellular (pHe). Raised pHi is thought be beneficial tumor progression invasiveness. However, transport mechanisms underpinning this adaptation have not been studied systematically. Here, we characterize pHe-pHi relationship in 66 colorectal cancer cell lines identify acid-loading anion exchanger 2 (AE2, SLC4A2) as a regulator resting pHi. Cells adapt chronic acidosis by degrading AE2 protein, which raises reduces acid sensitivity growth. Acidity inhibits mTOR signaling, stimulates lysosomal function degradation, process reversed bafilomycin A1. We degradation mechanism maintaining conducive tumors. As adaptive mechanism, inhibiting potential therapeutic target.

Language: Английский

---

Hyperforin Elicits Cytostatic/Cytotoxic Activity in Human Melanoma Cell Lines, Inhibiting Pro-Survival NF-κB, STAT3, AP1 Transcription Factors and the Expression of Functional Proteins Involved in Mitochondrial and Cytosolic Metabolism

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(2), P. 1263 - 1263

Published: Jan. 9, 2023

Hyperforin (HPF), the main component responsible for antidepressant action of Hypericum perforatum, displays additional beneficial properties including anti-inflammatory, antimicrobic, and antitumor activities. Among its effects, HPF activity on melanoma is poorly documented. Melanoma, especially BRAF-mutated melanoma, still a high-mortality tumor type currently available therapies do not provide solutions. We investigated HPF's antimelanoma effectiveness in A375, FO1 SK-Mel-28 human cell lines. Cell viability assays documented that all cells were affected by low concentrations (EC50% 2-4 µM) time-dependent manner. A Br-deoxy-uridine incorporation assay attested significant reduction proliferation accompanied decreased expression cyclin D1 A2, CDK4 Rb protein phosphorylation, as assessed immunoblots. In addition, P21/waf1 activated form P53 increased A375 cells. Furthermore, exerts cytotoxic effects. Apoptosis induced 24 h after administration, an increase cleaved-PARP1 decrease both Bcl2 Bcl-xL levels. Autophagy induced, augmented LC3B augmentation AMPK. Moreover, lowers GPX4 enzyme expression, suggesting ferroptosis induction. has been reported to activate TRPC6 Ca++ channel and/or Zn++ release from mitochondria stores, increasing cytosolic concentrations. Our data highlighted affects many cell-signaling pathways, signaling Ca++, such FRA1, pcJun pCREB, or which are shortly treatment. However, blockage use chelators hinder cytostatic/cytotoxic activity, damages may pass through other pathways. Remarkably, treatment, forms transcription factors NF-κB P65 subunit STAT3 significantly lowered. Several (PGM2, LDHA pPKM2) mitochondrial (UQCRC1, COX4 ATP5B) enzymes downregulated generalized vital functions line with these results recognized ability affect membrane potential acting protonophore. Finally, can migration colony formation soft agar. conclusion, we evidence pleiotropic effects

Language: Английский

---

LncRNA RP11-620J15.3 promotes HCC cell proliferation and metastasis by targeting miR-326/GPI to enhance glycolysis

Biology Direct, Journal Year: 2023, Volume and Issue: 18(1)

Published: April 5, 2023

Abstract Background Accumulating studies have demonstrated that the Warburg effect plays a central role in occurrence and development of hepatocellular carcinoma (HCC), albeit non-coding RNA (lncRNA) its association remains unclear. Methods The Zhengzhou University People’s Hospital kindly provided 80 pairs HCC tissues their matched paracancerous for this study. Bioinformatics analysis, real-time quantitative polymerase chain reaction, Western blotting, oncology functional assays were performed to determine contribution RP11-620J15.3 HCC. mechanism co-immunoprecipitation luciferase reporter gene was employed ascertain how interacts with important molecular targets. Results Our results revealed lncRNA termed overexpressed substantially associated tumor size. A high expression mRNA found be significantly worsening prognosis patients. We discovered stimulated glycolytic pathway cells by RNA-sequencing (RNA-seq) metabolomics analyses. Mechanistically, acted as competitive endogenous regulate GPI sponging miR-326 In addition, TBP transcription factor RP11-620J15.3, which contributed cells. Conclusion Based on our findings, is novel LncRNA positively regulates progression. Specifically, RP11-620J15.3/miR-326/GPI promotes malignant progression regulating glycolysis, thereby providing targets treatment drug development.

Language: Английский

---

Comprehensive bioinformatics analysis of the solute carrier family and preliminary exploration of SLC25A29 in lung adenocarcinoma

Cancer Cell International, Journal Year: 2023, Volume and Issue: 23(1)

Published: Sept. 29, 2023

According to the latest epidemiological investigation, lung adenocarcinoma (LUAD) is one of most fatal cancer among both men and women. Despite continuous advancements in treatment approaches recent years, prognosis for LUAD remains relatively poor. Given crucial role solute carrier (SLC) family maintaining cellular energy metabolism stability, we conducted a comprehensive analysis association between SLC genes prognosis. In present study, identified 71 members, which 32 were downregulated 39 upregulated samples. Based on these differentially expressed genes, prognostic risk scoring model was established that composed five (SLC16A7, SLC16A4, SLC16A3, SLC12A8, SLC25A15) clinical characteristics; this could effectively predict survival patients cohort. Notably, SLC2A1, SLC25A29, SLC27A4 as key associated with tumor stage. Further revealed SLC25A29 underexpressed tissue regulated phenotype endothelial cells. Endothelial cell proliferation migration increased apoptosis decreased decrease expression. Investigation upstream regulatory mechanisms expression gradually lactate concentration increased. This phenomenon suggested may be related lactylation modification. ChIP-qPCR experiments confirmed critical played by H3K14la H3K18la modifications promoter region SLC25A29. conclusion, study regulating phenotypes. These results provided important clues further understand pathogenesis develop appropriate therapeutic strategies.

Language: Английский

---

Glutamine Metabolism Promotes Renal Fibrosis through Regulation of Mitochondrial Energy Generation and Mitochondrial Fission

International Journal of Biological Sciences, Journal Year: 2024, Volume and Issue: 20(3), P. 987 - 1003

Published: Jan. 1, 2024

Fibroblast activation and proliferation is an essential phase in the progression of renal fibrosis.Despite recognized significance glutamine metabolism cellular growth proliferation, its precise pathophysiological relevance fibrosis remains uncertain.Therefore, this study aims to investigate involvement fibroblast possible mechanism.Our findings highlight importance reveal that patients with severe exhibit elevated serum levels increased expression kidney synthetase.Furthermore, deprivation vitro vivo could inhibit activation, thereby ameliorating fibrosis.It was also detected crucial for maintaining mitochondrial function morphology.These effects may partially depend on metabolic intermediate α-ketoglutaric acid.Moreover, led upregulated fission fibroblasts mammalian target rapamycin / process 1 dynamin-related protein pathway.Thus, these results provide compelling evidence modulation initiates regulation function, facilitating fibrosis.Consequently, targeting emerges as a novel promising avenue therapeutic intervention prevention fibrosis.

Language: Английский

---

Beyond basic research: the contribution of cathepsin B to cancer development, diagnosis and therapy

Expert Opinion on Therapeutic Targets, Journal Year: 2022, Volume and Issue: 26(11), P. 963 - 977

Published: Nov. 2, 2022

Introduction In view of other candidate proteins from the cathepsin family proteases holding great potential in being targeted during cancer therapy, importance Cathepsin B (CtsB) stands out as truly exceptional. Based on its contribution to oncogenesis, intimate connection with regulating apoptosis and modulating extracellular intracellular functions through secretion or compartmentalized subcellular localization, collectively highlight complex molecular involvement a myriad normal pathological regulatory processes. Despite functional nature, CtsB is emerging one few that has been extensively researched yield tangible outcomes for therapy.Areas covered this article, we review scientific literature justified shaped expression progression, perspective highlighting paradigm rapidly changing basic research toward broader clinical translational context.Expert opinion doing so, detail maturation diagnostic marker describing development CtsB-specific Activity-Based Probes, rapid evolution these new generation Prodrugs, evaluation model systems their therapeutic anti-cancer agents clinic.

Language: Английский

---