Andrographis-mediated chemosensitization through activation of ferroptosis and suppression of β-catenin/Wnt-signaling pathways in colorectal cancer

Sharma, Priyanka; Shimura, Takaya; Banwait, Jasjit K.; Goel, Ajay

doi:10.1093/carcin/bgaa090

Cited by 63 publications

(54 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The inhibition of GCLM will induce the ferroptosis. The gene expression profiles show the GCLM level is up-regulated in many tumors [ 33 , 34 ]. Moreover, the GCLM expression level is negatively associated with patients’ relapse-free survival (RFS) and OS [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…The existence of GLCM that drives ferroptosis has important implications for cancer therapy. A recent study by Sharma P identified the Andrographis, a medicine herb, could overcome the colorectal cancer chemoresistance by regulating the ferroptosis genes, such as GCLM [ 34 ]. Therefore, drugs that target ferroptosis can be exploited and provide an efficient strategy for clinical application.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Identification the ferroptosis-related gene signature in patients with esophageal adenocarcinoma

et al. 2021

View full text Add to dashboard Cite

Background Ferroptosis is a recently recognized non-apoptotic cell death that is distinct from the apoptosis, necroptosis and pyroptosis. Considerable studies have demonstrated ferroptosis is involved in the biological process of various cancers. However, the role of ferroptosis in esophageal adenocarcinoma (EAC) remains unclear. This study aims to explore the ferroptosis-related genes (FRG) expression profiles and their prognostic values in EAC. Methods The FRG data and clinical information were downloaded from The Cancer Genome Atlas (TCGA) database. Univariate and multivariate cox regressions were used to identify the prognostic FRG, and the predictive ROC model was established using the independent risk factors. GO and KEGG enrichment analyses were performed to investigate the bioinformatics functions of significantly different genes (SDG) of ferroptosis. Additionally, the correlations of ferroptosis and immune cells were assessed through the single-sample gene set enrichment analysis (ssGSEA) and TIMER database. Finally, SDG were verified in clinical EAC specimens and normal esophageal mucosal tissues. Results Twenty-eight significantly different FRG were screened from 78 EAC and 9 normal tissues. Enrichment analyses showed these SDG were mainly related to the iron-related pathways and metabolisms of ferroptosis. Gene network demonstrated the TP53, G6PD, NFE2L2 and PTGS2 were the hub genes in the biology of ferroptosis. Cox regression analyses demonstrated four FRG (CARS1, GCLM, GLS2 and EMC2) had prognostic values for overall survival (OS) (all P < 0.05). ROC curve showed better predictive ability using the risk score (AUC = 0.744). Immune cell enrichment analysis demonstrated that the types of immune cells and their expression levels in the high-risk group were significant different with those in the low-risk group (all P < 0.05). The experimental results confirmed the ALOX5, NOX1 were upregulated and the MT1G was downregulated in the EAC tissues compared with the normal esophageal mucosal tissues (all P < 0.05). Conclusions We identified differently expressed ferroptosis-related genes that may involve in EAC. These genes have significant values in predicting the patients’ OS and targeting ferroptosis may be an alternative for therapy. Further studies are necessary to verify these results of our study.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification the ferroptosis-related gene signature in patients with esophageal adenocarcinoma

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Aspirin dosing in our CD1 Nude mouse model [ 36 , 37 ], which mimicked low-dose aspirin use in humans, based on profound platelet COX-1 inhibition but an absence of systemic COX-2 inhibition, did not increase the sensitivity of MC38 mouse CRC cell tumours to EPA in vivo, in direct contrast to the corresponding in vitro data. We demonstrated that there was inefficient inhibition of PGE 2 production in CRC cell tumour tissue, despite efficient systemic COX-1 inhibition.…”

Section: Discussionmentioning

confidence: 99%

Cyclooxygenase activity mediates colorectal cancer cell resistance to the omega-3 polyunsaturated fatty acid eicosapentaenoic acid

Volpato

Ingram

Perry

et al. 2020

Cancer Chemother Pharmacol

View full text Add to dashboard Cite

Purpose The naturally-occurring omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) is safe, well-tolerated and inexpensive, making it an attractive anti-cancer intervention. However, EPA has only modest anti-colorectal cancer (CRC) activity, when used alone. Both cyclooxygenase (COX) isoforms metabolise EPA and are over-expressed in CRC cells. We investigated whether COX inhibition increases the sensitivity of CRC cells to growth inhibition by EPA. Methods A panel of 18 human and mouse CRC cell lines was used to characterize the differential sensitivity of CRC cells to the growth inhibitory effects of EPA. The effect of CRISPR-Cas9 genetic deletion and pharmacological inhibition of COX-1 and COX-2 on the anti-cancer activity of EPA was determined using in vitro and in vivo models. Results Genetic ablation of both COX isoforms increased sensitivity of CT26 mouse CRC cells to growth inhibition by EPA in vitro and in vivo. The non-selective COX inhibitor aspirin and the selective COX-2 inhibitor celecoxib increased sensitivity of several human and mouse CRC cell lines to EPA in vitro. However, in a MC38 mouse CRC cell tumour model, with dosing that mirrored low-dose aspirin use in humans, thereby producing significant platelet COX-1 inhibition, there was ineffective intra-tumoral COX-2 inhibition by aspirin and no effect on EPA sensitivity of MC38 cell tumours. Conclusion Cyclooxygenase inhibition by non-steroidal anti-inflammatory drugs represents a therapeutic opportunity to augment the modest anti-CRC activity of EPA. However, intra-tumoral COX inhibition is likely to be critical for this drug-nutrient interaction and careful tissue pharmacodynamic profiling is required in subsequent pre-clinical and human studies.

show abstract

“…The inhibition of GCLM will induce the ferroptosis. The gene expression pro les show the GCLM level is up-regulated in many tumors [33][34] . Moreover, the GCLM expression level is negatively associated with patients' relapse free survival (RFS) and OS [33] .…”

Section: Discussionmentioning

confidence: 99%

“…The existence of GLCM that drives ferroptosis has important implications for cancer therapy. A recent study by Sharma P identi ed the Andrographis, a medicine herb, could overcome the colorectal cancer chemoresistance by regulating the ferroptosis genes, such as GCLM [34] . Therefore, drugs that target ferroptosis can be exploited and provide an e cient strategy for clinical application.…”

Section: Discussionmentioning

confidence: 99%

Identification the Roles of Ferroptosis-Related Gene Signatures in Patients with Esophageal Adenocarcinoma

Yang

Wang

Dong

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Ferroptosis is a recently recognized non-apoptotic cell death that is distinct from the apoptosis, necroptosis and pyroptosis. Considerable studies have demonstrated ferroptosis is involved in the biological process of various cancers. However, the role of ferroptosis in esophageal adenocarcinoma (EAC) remains unclear. The aim of this study was to explore the ferroptosis-related genes (FRG) expression profiles and their prognostic values in EAC.Methods The FRG data and clinical information were downloaded from The Cancer Genome Atlas (TCGA) database. Univariate and multivariate cox regressions were used to identify the prognostic FRG, and the predictive ROC model was established using the independent risk factors. GO and KEGG enrichment analyses were performed to investigate the bioinformatics functions of significantly different genes (SDG) of ferroptosis. Additionally, the correlations of ferroptosis and immune cells were assessed through the single-sample gene set enrichment analysis (ssGSEA). Finally, significantly different genes were verified in our clinical EAC specimens and normal esophageal mucosal tissues.Results: Twenty-eight significantly different FRG were screened from 78 EAC and 9 normal tissues. GO and KEGG enrichments showed these SDG were mainly related to the iron-related pathways and metabolisms of ferroptosis. Gene network demonstrated the TP53, G6PD, NFE2L2 and PTGS2 were the hub genes in the biology of ferroptosis. Cox regression analyses demonstrated four FRG (CARS1, GCLM, GLS2 and EMC2) had prognostic values for overall survival (OS) (all P<0.001). ROC curves showed better efficacy to predict survival using the risk score (AUC=0.744). Immune cell enrichment analysis demonstrated that the types of immune cells and their expression levels in the high-risk group were significant different with those in the low-risk group (all P<0.05). The experimental results confirmed the ALOX5, NOX1 were upregulated and the MT1G was downregulated in the EAC tissues compared with the normal esophageal mucosal tissues (all P<0.05).Conclusions: We identified differently expressed ferroptosis-related genes that may involve in the process in EAC. These genes have significant values in predicting the patients’ OS and targeting ferroptosis may be an alternative for therapy. Further studies are necessary to verify these results of our study.

show abstract

Andrographis-mediated chemosensitization through activation of ferroptosis and suppression of β-catenin/Wnt-signaling pathways in colorectal cancer

Cited by 63 publications

References 55 publications

Identification the ferroptosis-related gene signature in patients with esophageal adenocarcinoma

Identification the ferroptosis-related gene signature in patients with esophageal adenocarcinoma

Cyclooxygenase activity mediates colorectal cancer cell resistance to the omega-3 polyunsaturated fatty acid eicosapentaenoic acid

Identification the Roles of Ferroptosis-Related Gene Signatures in Patients with Esophageal Adenocarcinoma

Contact Info

Product

Resources

About