Relationship between colorectal cancer glutathione levels and patient survival

2000 ◽  
Vol 43 (8) ◽  
pp. 1133-1140 ◽  
Author(s):  
Sam C. Barranco ◽  
Roger R. Perry ◽  
Mary E. Durm ◽  
Mohammed Quraishi ◽  
Alice L. Werner ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Patient Survival

scholarly journals The loss of SHMT2 mediates 5-fluorouracil chemoresistance in colorectal cancer by upregulating autophagy

Oncogene ◽  
2021 ◽  
Author(s):  
Jian Chen ◽  
Risi Na ◽  
Chao Xiao ◽  
Xiao Wang ◽  
Yupeng Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Patient Survival ◽  
Serine Hydroxymethyltransferase ◽  
First Line ◽  
Xenograft Models ◽  
Potential Opportunity ◽  
First Line Treatment ◽  
Novel Therapeutic

Abstract5-Fluorouracil (5-FU)-based chemotherapy is the first-line treatment for colorectal cancer (CRC) but is hampered by chemoresistance. Despite its impact on patient survival, the mechanism underlying chemoresistance against 5-FU remains poorly understood. Here, we identified serine hydroxymethyltransferase-2 (SHMT2) as a critical regulator of 5-FU chemoresistance in CRC. SHMT2 inhibits autophagy by binding cytosolic p53 instead of metabolism. SHMT2 prevents cytosolic p53 degradation by inhibiting the binding of p53 and HDM2. Under 5-FU treatment, SHMT2 depletion promotes autophagy and inhibits apoptosis. Autophagy inhibitors decrease low SHMT2-induced 5-FU resistance in vitro and in vivo. Finally, the lethality of 5-FU treatment to CRC cells was enhanced by treatment with the autophagy inhibitor chloroquine in patient-derived and CRC cell xenograft models. Taken together, our findings indicate that autophagy induced by low SHMT2 levels mediates 5-FU resistance in CRC. These results reveal the SHMT2–p53 interaction as a novel therapeutic target and provide a potential opportunity to reduce chemoresistance.

The Clinical and Prognostic Significance of Protein Arginine Deiminases 2 and 4 in Colorectal Cancer

Pathobiology ◽  
2021 ◽  
pp. 1-11
Author(s):  
Mohamed Gijon ◽  
Rachael L. Metheringham ◽  
Michael S. Toss ◽  
Samantha J. Paston ◽  
Lindy G. Durrant
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Survival Time ◽  
Patient Survival ◽  
Prognostic Significance ◽  
High Expression ◽  
Related Protein ◽  
Post Translational Modification

<b><i>Introduction:</i></b> Protein arginine deiminases (PADIs) are a family of enzymes that catalyse the post-translational modification of proteins. Association between PADI expression and clinicopathology, protein expression, and outcome was determined. <b><i>Methods:</i></b> PADI2 and PADI4 expression was assessed immunohistochemically in a cohort of colorectal cancer (CRC) patients. <b><i>Results:</i></b> CRC tissues expressed variable levels of PADI2 which was mainly localised in the cytoplasm and correlated with patient survival (<i>p</i> = 0.005); high expression increased survival time from 43.5 to 67.6 months. Expression of cytoplasmic PADI2 correlated with the expression of nuclear β catenin, PADI4, and alpha-enolase. In contrast, expression of nuclear PADI2 correlated with a decrease in survival (<i>p</i> = 0.010), with high expression decreasing survival from 76.4 to 42.9 months. CRC tissues expressed variable levels of PADI4 in both the nucleus and cytoplasm. Expression of cytoplasmic PADI4 correlated with survival (<i>p</i> = 0.001) with high expression increasing survival time from 48.1 to 71.8 months. Expression of cytoplasmic PADI4 correlated with expression of nuclear β catenin, alpha-enolase (<i>p</i> ≤ 0.0001, <i>p</i> = 0.002), and the apoptotic related protein, Bcl-2. Expression of nuclear PADI4 also correlated with survival (<i>p</i> = 0.011), with high expression of nuclear PADI4 increasing survival time from 55.4 to 74 months. Expression of nuclear PADI4 correlated with p53, alpha-enolase, and Bcl-2. Multivariate analysis showed that TNM stage, cytoplasmic PADI2, and PADI4 remained independent prognostic factors in CRC. Both PADI2 and PADI4 are good prognostic factors in CRC. <b><i>Conclusion:</i></b> High expression of cytoplasmic PADI2, PADI4, and nuclear PADI4 were associated with an increase in overall survival.

scholarly journals Improvement of Metastatic Colorectal Cancer Patient Survival: Single Institution Experience

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 369 ◽  
Author(s):  
Elisabetta Fenocchio ◽  
Federica Colombi ◽  
Maria Grazia Calella ◽  
Roberto Filippi ◽  
Ilaria Depetris ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Patient Survival ◽  
Colorectal Cancer Patient ◽  
Survival Rates ◽  
Integrated Approach ◽  
Metastatic Tumour ◽  
Single Institution ◽  
Significant Difference ◽  
Metastatic Colorectal Cancer Patient

The survival rates of patients with metastatic colorectal cancer (mCRC) have improved in recent years. We analysed the survival of mCRC patients followed at a single institution over the last 17 years. We retrospectively collected data from 899 mCRC patients treated from 2001 to 2016. Patients were divided into two groups based on the year of diagnosis: Cohort A (2001–2006) and Cohort B (2007–2014). A total of 788 patients were analysed. The median survival of the whole population was 32.0 months with a significant difference between Cohort A and B (29.2 vs. 33.5 months; p = 0.041). Surgical procedures significantly increased in Cohort B, however, no significant changes in survival were observed in patients undergoing surgery (58.9 months Cohort A vs. 58.2 months Cohort B, p = 0.822). Similarly, we did not demonstrate survival improvement in patients treated with systemic therapy alone (18.9 months Cohort A vs. 20.7 months Cohort B; p = 0.948). At the multivariate analysis, right-sided primary and synchronous metastatic tumour were found to be independent unfavorable prognostic factors. Improvements of mCRC patient survival might relate to integrated approach, with more patients undergoing extra-hepatic surgery. The medical approach seems to have had a more favourable impact on subgroups characterized by a worse prognosis.

scholarly journals Expression of HTRA Genes and Its Association with Microsatellite Instability and Survival of Patients with Colorectal Cancer

2020 ◽  
Vol 21 (11) ◽  
pp. 3947
Author(s):  
Dorota Zurawa-Janicka ◽  
Jarek Kobiela ◽  
Tomasz Slebioda ◽  
Rafal Peksa ◽  
Marcin Stanislawowski ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Survival Data ◽  
Patient Survival ◽  
Mrna Level ◽  
Metastatic Potential ◽  
Colorectal Carcinogenesis ◽  
Cancer Tissue ◽  
Protein Levels ◽  
High Level

HtrA proteases regulate cellular homeostasis and cell death. Their dysfunctions have been correlated with oncogenesis and response to therapeutic treatment. We investigated the relation between HtrA1-3 expression and clinicopathological, and survival data, as well as the microsatellite status of tumors. Sixty-five colorectal cancer patients were included in the study. The expression of HTRA1-3 was estimated at the mRNA and protein levels by quantitative PCR and immunoblotting. Microsatellite status was determined by high-resolution-melting PCR. We found that the HTRA1 mRNA level was higher in colorectal cancer tissue as compared to the unchanged mucosa, specifically in primary lesions of metastasizing cancer. The levels of HtrA1 and HtrA2 proteins were reduced in tumor tissue when compared to unchanged mucosa, specifically in primary lesions of metastasizing disease. Moreover, a decrease in HTRA1 and HTRA2 transcripts’ levels in cancers with a high level of microsatellite instability compared to microsatellite stable ones has been observed. A low level of HtrA1 or/and HtrA2 in cancer tissue correlated with poorer patient survival. The expression of HTRA1 and HTRA2 changes during colorectal carcinogenesis and microsatellite instability may be, at least partially, associated with these changes. The alterations in the HTRA1/2 genes’ expression are connected with metastatic potential of colorectal cancer and may affect patient survival.

scholarly journals Alterations of the Hsp70/Hsp90 chaperone and the HOP/CHIP co-chaperone system in cancer

2012 ◽  
Vol 17 (3) ◽  
Author(s):  
Eva Ruckova ◽  
Petr Muller ◽  
Rudolf Nenutil ◽  
Borivoj Vojtesek
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Binding Sites ◽  
Patient Survival ◽  
Proliferating Cells ◽  
Response Elements ◽  
Over Expression ◽  
Hsp90 Activity ◽  
Hsp90 Chaperone ◽  
Client Proteins

AbstractActivation of the Hsp90 chaperone system is a characteristic of cancer cells. The regulation of chaperone activities involves their interaction with cochaperones; therefore we investigated the expression of Hsp70 and Hsp90 and their specific co-chaperones HOP and CHIP in cancer cell lines and primary cancers. Inhibition of Hsp90 by 17AAG increased the levels of Hsp70, Hsp90 and HOP but not CHIP mRNA in cancer cells. These changes are linked to activation of the HSF1 transcription factor and we show that the HOP promoter contains HSF1 binding sites, and that HSF1 binding to the HOP promoter is increased following 17AAG. The lack of alteration in the co-chaperone CHIP is explained by a lack of HSF response elements in the CHIP promoter. Non-proliferating cells expressed higher levels of CHIP and lower HOP, Hsp70 and Hsp90 levels compared to proliferating cells. Decreased expression of CHIP in proliferating cancer cells is in keeping with its proposed tumor suppressor properties, while over-expression of HOP in proliferating cells may contribute to excessive Hsp90 activity and stabilization of client proteins in tumors. In a panel of colorectal cancer samples, increased expression of Hsp70 and an increased ratio of HOP to CHIP were found, and were associated with decreased median survival. These data indicate that multiple changes occur in the chaperone/co-chaperone system in cancer that impact patient survival. It is likely that the ability to identify individual alterations to this system will be beneficial for treatment strategy decisions, particularly those that employ chaperone inhibitors.

Increased expression of thioredoxin-1 in human colorectal cancer is associated with decreased patient survival

2003 ◽  
Vol 142 (1) ◽  
pp. 46-51 ◽  
Author(s):  
Jennifer Raffel ◽  
Achyut K. Bhattacharyya ◽  
Alfred Gallegos ◽  
Haiyan Cui ◽  
Janine G. Einspahr ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Patient Survival ◽  
Human Colorectal Cancer ◽  
Thioredoxin 1

Su2003 Significance of EMAST/MSI-L and Chromosome 9p24.2 Loss of Heterozygosity (LOH) for Patient Survival With Stage II/III Colorectal Cancer (CRC)

2016 ◽  
Vol 150 (4) ◽  
pp. S607
Author(s):  
Minoru Koi ◽  
Melissa Garcia ◽  
Chan Choi ◽  
Hyeong-Rok Kim ◽  
Junichi Koike ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Loss Of Heterozygosity ◽  
Patient Survival ◽  
Stage Ii
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