Strategies to target energy metabolism in consensus molecular subtype 3 along with Kirsten rat sarcoma viral oncogene homolog mutations for colorectal cancer therapy

Wang, Gang; Wang, Junjie; Yin, Peihao; Xu, Kecheng; Wang, Yuzhu; Shi, Feng; Gao, Jing; Fu, Xiaohong

doi:10.1002/jcp.27388

Cited by 8 publications

(7 citation statements)

References 104 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have previously described an energy metabolism network link between KRAS-mutant CRC and multiple metabolic pathways, including lipids, amino acids, FA metabolism and glycolysis, and several factors and metabolic genes, such as alanine, serine, cysteine-preferring transporter 2, stearoyl-CoA desaturase (SCD), FASN, ACSL, c-Myc, glutaminase-1, ATP-binding cassette subfamily A member 1, glucose transporter 1, asparagine synthetase and 1-acylglycerol-3-phosphate O-acyltransferase 1. These factors induce metabolic changes and regulate metabolic pathways together with major energy sources associated with mutant KRAS, and they are often overexpressed in CRC patients with poor prognosis ( 38 ). ACSL1 is involved in lipid synthesis, modification and β-oxidation; and SCD is the main enzyme controlling the rate of conversion of saturated FA to monounsaturated FA ( 39 ), which is crucial for cancer cells ( 40 ).…”

Section: Discussionmentioning

confidence: 99%

Effects and mechanisms of fatty acid metabolism‑mediated glycolysis regulated by betulinic acid‑loaded nanoliposomes in colorectal cancer

Wang

et al. 2020

Oncol Rep

Self Cite

View full text Add to dashboard Cite

Although previous studies have demonstrated that triterpenoids, such as betulinic acid (BA), can inhibit tumor cell growth, their potential targets in colorectal cancer (CRC) metabolism have not been systematically investigated. In the present study, BA-loaded nanoliposomes (BA-NLs) were prepared, and their effects on CRC cell lines were evaluated. The aim of the present study was to determine the anticancer mechanisms of action of BA-NLs in fatty acid metabolism-mediated glycolysis, and investigate the role of key targets, such as acyl-CoA synthetase (ACSL), carnitine palmitoyltransferase (CPT) and acetyl CoA, in promoting glycolysis, which is activated by inducing hexokinase (HK), phosphofructokinase-1 (PFK-1), phosphoenolpyruvate (PEP) and pyruvate kinase (PK) expression. The results demonstrated that BA-NLs significantly suppressed the proliferation and glucose uptake of CRC cells by regulating potential glycolysis and fatty acid metabolism targets and pathways, which forms the basis of the anti-CRC function of BA-NLs. Moreover, the effects of BA-NLs were further validated by demonstrating that the key targets of HK2, PFK-1, PEP and PK isoenzyme M2 (PKM2) in glycolysis, and of ACSL1, CPT1a and PEP in fatty acid metabolism, were blocked by BA-NLs, which play key roles in the inhibition of glycolysis and fatty acid-mediated production of pyruvate and lactate. The results of the present study may provide a deeper understanding supporting the hypothesis that liposomal BA may regulate alternative metabolic pathways implicated in CRC adjuvant therapy.

show abstract

Section: Discussionmentioning

confidence: 99%

Effects and mechanisms of fatty acid metabolism‑mediated glycolysis regulated by betulinic acid‑loaded nanoliposomes in colorectal cancer

Wang

et al. 2020

Oncol Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…We have previously described an energy metabolism network link between KRAS-mutant CRC and multiple metabolism, including glycolysis associated with KRAS status alongside factors and metabolic genes. These metabolic genes and factors induce metabolic changes and regulate energy metabolic pathways together with major energy sources associated with mutant KRAS, often overexpressing in patients with poor prognosis of CRC [43]. It has shown that there is high level of glycolysis in the CRC cell line (HCT116).…”

Section: Discussionmentioning

confidence: 99%

The effects and mechanisms of isoliquiritigenin loaded nanoliposomes regulated AMPK/mTOR mediated glycolysis in colorectal cancer

Wang

et al. 2020

Artificial Cells, Nanomedicine, and Biotechnology

Self Cite

View full text Add to dashboard Cite

In this study, isoliquiritigenin (ISL) incorporated nanoliposomes were prepared and their effects on colorectal cancer (CRC) cell lines were investigated. Herein, we sought to explore the anti-cancer mechanisms of ISL loaded nanoliposomes (ISL-NLs) on AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) pathways mediated glycolysis. Also, the key targets such as caveolin 1 (CAV1), glucose transporters and Akt/mTOR that promote glycolysis, and are activated via the induction of a-enolase (ENO1), fructose bisphosphate aldolase A (ALDOA) and monocarboxylate transporter 4 (MCT4) expressions were also investigated. It was shown that ISL-NLs significantly suppressed the proliferation and glucose uptake of CRC cell by potentially regulating the glycolysis and lactate targets as well as pathways that formed the basis of the anti-CRC effects of ISL-NLs. The mechanism underlying this effect was further validated via the regulation of some key targets such as ENO1, ALDOA, lactate dehydrogenase A (LDHA) and MCT4 in glycolysis coupled with cellular myelocytomatosis oncogene (cmyc), hypoxia-inducible factor 1-alpha (HIF-1a) in protein kinase B/mTOR (Akt/mTOR) pathways. Moreover, the AMPK proteins were identified to be up-regulated while the lactic acid production was suppressed by ISL-NLs in the CRC cells, indicating that ISL-NLs had an inhibitory effect on AMPK mediated glycolysis and lactate production. Altogether, these results have provided insights into the mechanism underlying the key role that liposomal ISL played in the multiple inhibition of AMPK and Akt/ mTOR mediated glycolysis and lactate generation, which may be regulated as the alternative metabolic pathways of CRC as well as serve as adjuvant therapy for the disease.

show abstract

“…Metabolic reprogramming contributes to tumor development, metastasis and drug resistance. Therefore, others and we have proposed to exploit the metabolic liabilities to treat cancers [13,[37][38][39][40][41][42].…”

Section: Discussionmentioning

confidence: 99%

Discovery of Novel Inhibitors Targeting Multi-UDP-hexose Pyrophosphorylases as Anticancer Agents

et al. 2020

View full text Add to dashboard Cite

To minimize treatment toxicities, recent anti-cancer research efforts have switched from broad-based chemotherapy to targeted therapy, and emerging data show that altered cellular metabolism in cancerous cells can be exploited as new venues for targeted intervention. In this study, we focused on, among the altered metabolic processes in cancerous cells, altered glycosylation due to its documented roles in cancer tumorigenesis, metastasis and drug resistance. We hypothesize that the enzymes required for the biosynthesis of UDP-hexoses, glycosyl donors for glycan synthesis, could serve as therapeutic targets for cancers. Through structure-based virtual screening and kinetic assay, we identified a drug-like chemical fragment, GAL-012, that inhibit a small family of UDP-hexose pyrophosphorylases-galactose pyro-phosphorylase (GALT), UDP-glucose pyrophosphorylase (UGP2) and UDP-N-acetylglucosamine pyrophosphorylase (AGX1/UAP1) with an IC50 of 30 µM. The computational docking studies supported the interaction of GAL-012 to the binding sites of GALT at Trp190 and Ser192, UGP2 at Gly116 and Lys127, and AGX1/UAP1 at Asn327 and Lys407, respectively. One of GAL-012 derivatives GAL-012-2 also demonstrated the inhibitory activity against GALT and UGP2. Moreover, we showed that GAL-012 suppressed the growth of PC3 cells in a dose-dependent manner with an EC50 of 75 µM with no effects on normal skin fibroblasts at 200 µM. Western blot analysis revealed reduced expression of pAKT (Ser473), pAKT (Thr308) by 77% and 72%, respectively in the treated cells. siRNA experiments against the respective genes encoding the pyrophosphorylases were also performed and the results further validated the proposed roles in cancer growth inhibition. Finally, synergistic relationships between GAL-012 and tunicamycin, as well as bortezomib (BTZ) in killing cultured cancer cells were observed, respectively. With its unique scaffold and relatively small size, GAL-012 serves as a promising early chemotype for optimization to become a safe, effective, multi-target anti-cancer drug candidate which could be used alone or in combination with known therapeutics.

show abstract

Strategies to target energy metabolism in consensus molecular subtype 3 along with Kirsten rat sarcoma viral oncogene homolog mutations for colorectal cancer therapy

Cited by 8 publications

References 104 publications

Effects and mechanisms of fatty acid metabolism‑mediated glycolysis regulated by betulinic acid‑loaded nanoliposomes in colorectal cancer

Effects and mechanisms of fatty acid metabolism‑mediated glycolysis regulated by betulinic acid‑loaded nanoliposomes in colorectal cancer

The effects and mechanisms of isoliquiritigenin loaded nanoliposomes regulated AMPK/mTOR mediated glycolysis in colorectal cancer

Discovery of Novel Inhibitors Targeting Multi-UDP-hexose Pyrophosphorylases as Anticancer Agents

Contact Info

Product

Resources

About