Altered glycolysis results in drug‑resistant in clinical tumor therapy (Review) DOI Open Access
Jinghui Peng, Yangyang Cui, Shipeng Xu

et al.

Oncology Letters, Journal Year: 2021, Volume and Issue: 21(5)

Published: March 11, 2021

Cancer cells undergo metabolic reprogramming, including increased glucose metabolism, fatty acid synthesis and glutamine rates. These enhancements to three major pathways are closely associated with glycolysis, which is considered the central component of cancer cell metabolism. Increasing evidence suggests that dysfunctional glycolysis commonly drug resistance in treatment, aberrant plays a significant role drug‑resistant cells. Studies on development drugs targeting these abnormalities have led improvements efficacy tumor treatment. The present review discusses changes targets cause cells, hexokinase, pyruvate kinase, dehydrogenase complex, transporters, lactate, as well underlying molecular mechanisms corresponding novel therapeutic strategies. In addition, association between oxidative phosphorylation introduced, caused by plasticity. Given has been identified common feature may be strategy develop new benefit patients drug‑resistance.

Language: Английский

The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects DOI Creative Commons

Weiwei Tang,

Ziyi Chen, Wenling Zhang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2020, Volume and Issue: 5(1)

Published: June 10, 2020

Sorafenib is a multikinase inhibitor capable of facilitating apoptosis, mitigating angiogenesis and suppressing tumor cell proliferation. In late-stage hepatocellular carcinoma (HCC), sorafenib currently an effective first-line therapy. Unfortunately, the development drug resistance to becoming increasingly common. This study aims identify factors contributing ways mitigate resistance. Recent studies have shown that epigenetics, transport processes, regulated death, microenvironment are involved in HCC subsequent progression. summarizes discoveries achieved recently terms principles outlines approaches suitable for improving therapeutic outcomes patients.

Language: Английский

Citations

759
The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma DOI Creative Commons
Shunjie Xia, Yu Pan, Yuelong Liang

et al.

EBioMedicine, Journal Year: 2020, Volume and Issue: 51, P. 102610 - 102610

Published: Jan. 1, 2020

In most cases, sorafenib-resistant HCC cells exhibit significant mesenchymal phenotype and stemness features. this context, tumor might undergo cell fate transition in response to sorafenib or other targeted drugs the presence absence of genetic mutations. Therefore, understanding major characteristics drug-resistant state helps discover new treatments that overcome drug resistance. To note, little is known about metabolic microenvironmental aspects certain states beyond genome. This review mainly focuses on underlying mechanisms acquired resistance based CSCs EMT models, which explain heterogeneity have been considered cause secondary particular, it discusses how microenvironment metabolism regulate stemness, state, through epigenetic regulations, provides reliable targets synergetic effect with sorafenib.

Language: Английский

Citations

223
Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis DOI Creative Commons
Jiao Feng, Weiqi Dai, Yuqing Mao

et al.

Journal of Experimental & Clinical Cancer Research, Journal Year: 2020, Volume and Issue: 39(1)

Published: Jan. 30, 2020

Hepatocellular carcinoma (HCC) is a common primary malignant tumor which usually progresses to an advanced stage because of late diagnosis. Sorafenib (Sora) first line medicine for HCC; however, it has been faced with enormous resistance. Simvastatin (Sim) cholesterol-lowering drug and reported inhibit growth. The present study aims determine whether Sora Sim co-treatment can improve resistance in HCC.The HCC cell LM3 established Sora-resistant (LM3-SR) were used the relationship between aerobic glycolysis. Cell proliferation, apoptosis glycolysis levels analyzed by western blotting, flow cytometry analysis biomedical tests. A xenograft model was also examine effect vivo. Detailed mechanistic studies undertaken use activators inhibitors, lentivirus transfections.Our results demonstrated that associated enhanced levels. Furthermore, LM3-SR cells more sensitive than cells, suggesting combined treatment both could enhance sensitivity Sora. This finding may be due suppression HIF-1α/PPAR-γ/PKM2 axis.Simvastatin axis, suppressing PKM2-mediated glycolysis, resulting decreased proliferation increased re-sensitizing

Language: Английский

Citations

167
Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management DOI Creative Commons
Ping Jin, Jingwen Jiang, Li Zhou

et al.

Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)

Published: July 18, 2022

Drug resistance represents a major obstacle in cancer management, and the mechanisms underlying stress adaptation of cells response to therapy-induced hostile environment are largely unknown. As central organelle for cellular energy supply, mitochondria can rapidly undergo dynamic changes integrate signaling pathways provide bioenergetic biosynthetic flexibility cells, which contributes multiple aspects tumor characteristics, including drug resistance. Therefore, targeting therapy overcoming has attracted increasing attention various types cancer. Multiple mitochondrial processes, dynamics, metabolism, apoptotic regulatory machinery, have been demonstrated be potential targets. However, recent insights into revealed complexity structure functions, elusive functions biology, inaccessibility mitochondria, posed challenges clinical application mitochondrial-based therapeutic strategies. discovery both novel mitochondria-targeting agents innovative approaches is urgently required. Here, we review most literature summarize molecular their intricate connection with In addition, an overview emerging strategies target effectively chemoresistance highlighted, emphasis on repositioning delivery approaches, may accelerate compounds therapy.

Language: Английский

Citations

122
Protein post-translational modifications in the regulation of cancer hallmarks DOI
Haiying Wang, Liqian Yang, Minghui Liu

et al.

Cancer Gene Therapy, Journal Year: 2022, Volume and Issue: 30(4), P. 529 - 547

Published: April 7, 2022

Language: Английский

Citations

79
PRMT3-mediated arginine methylation of IGF2BP1 promotes oxaliplatin resistance in liver cancer DOI Creative Commons

Yunxing Shi,

Yi Niu,

Yichuan Yuan

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: April 6, 2023

Abstract Although oxaliplatin-based chemotherapy has been effective in the treatment of hepatocellular carcinoma (HCC), primary or acquired resistance to oxaliplatin remains a major challenge clinic. Through functional screening using CRISPR/Cas9 activation library, transcriptomic profiling clinical samples, and validation vitro vivo, we identify PRMT3 as key driver resistance. Mechanistically, PRMT3-mediated oxaliplatin-resistance is part dependent on methylation IGF2BP1 at R452, which critical for function stabilizing mRNA HEG1, an effector PRMT3-IGF2BP1 axis. Also, overexpression may serve biomarker HCC patients. Collectively, our study defines PRTM3-IGF2BP1-HEG1 axis important regulators therapeutic targets suggests potential use expression level pretreatment biopsy

Language: Английский

Citations

56
Targeting the Warburg effect: A revisited perspective from molecular mechanisms to traditional and innovative therapeutic strategies in cancer DOI Creative Commons

Minru Liao,

Dahong Yao,

Lifeng Wu

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2023, Volume and Issue: 14(3), P. 953 - 1008

Published: Dec. 16, 2023

Cancer reprogramming is an important facilitator of cancer development and survival, with tumor cells exhibiting a preference for aerobic glycolysis beyond oxidative phosphorylation, even under sufficient oxygen supply condition. This metabolic alteration, known as the Warburg effect, serves significant indicator malignant transformation. The effect primarily impacts occurrence by influencing pathway in cells. Key enzymes involved this process include glucose transporters (GLUTs), HKs, PFKs, LDHs, PKM2. Moreover, expression transcriptional regulatory factors proteins, such FOXM1, p53, NF-

Language: Английский

Citations

49
Nucleolin lactylation contributes to intrahepatic cholangiocarcinoma pathogenesis via RNA splicing regulation of MADD DOI Creative Commons
Yang Long,

Kunwei Niu,

Jianlin Wang

et al.

Journal of Hepatology, Journal Year: 2024, Volume and Issue: unknown

Published: April 1, 2024

Intrahepatic cholangiocarcinoma (iCCA) is a fatal malignancy of the biliary system. The lack detailed understanding oncogenic signaling or global gene expression alterations has impeded clinical iCCA diagnosis and therapy. role protein lactylation, newly unraveled post-translational modification that orchestrates expression, remains largely elusive in pathogenesis iCCA.

Language: Английский

Citations

30
New insights on sorafenib resistance in liver cancer with correlation of individualized therapy DOI
Cheng Zhang,

Weiqi Jiang,

Jin Ding

et al.

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2020, Volume and Issue: 1874(1), P. 188382 - 188382

Published: June 6, 2020

Language: Английский

Citations

95
Celastrol mitigates inflammation in sepsis by inhibiting the PKM2-dependent Warburg effect DOI Creative Commons
Piao Luo, Qian Zhang, Tianyu Zhong

et al.

Military Medical Research, Journal Year: 2022, Volume and Issue: 9(1)

Published: May 20, 2022

Abstract Background Sepsis involves life-threatening organ dysfunction and is caused by a dysregulated host response to infection. No specific therapies against sepsis have been reported. Celastrol (Cel) natural anti-inflammatory compound that shows potential systemic inflammatory diseases. This study aimed investigate the pharmacological activity molecular mechanism of Cel in models endotoxemia sepsis. Methods We evaluated efficacy mice macrophage cultures treated with lipopolysaccharide (LPS). screened for protein targets using activity-based profiling (ABPP). Potential were validated biophysical methods such as cellular thermal shift assays (CETSA) surface plasmon resonance (SPR). Residues involved binding target proteins identified through point mutagenesis, functional effects explored gene knockdown. Results protected from lethal improved their survival sepsis, it significantly decreased levels pro-inflammatory cytokines macrophages LPS ( P < 0.05). bound Cys424 pyruvate kinase M2 (PKM2), inhibiting enzyme thereby suppressing aerobic glycolysis (Warburg effect). also Cys106 high mobility group box 1 (HMGB1) protein, reducing secretion cytokine interleukin (IL)-1β. Cys residues lactate dehydrogenase A (LDHA). Conclusion inhibits inflammation Warburg effect via targeting PKM2 HMGB1 protein.

Language: Английский

Citations

68