scholarly journals Metabonomics study of the effects of single copy mutant KRAS in the presence or absence of WT allele using human HCT116 isogenic cell lines

Metabolomics ◽  
2021 ◽  
Vol 17 (12) ◽  
Author(s):  
Dorna Varshavi ◽  
Dorsa Varshavi ◽  
Nicola McCarthy ◽  
Kirill Veselkov ◽  
Hector C. Keun ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Single Point ◽  
Hct116 Cell ◽  
Cellular Transformation ◽  
Single Copy ◽  
Driver Mutations ◽  
Glutathione Metabolism ◽  
Single Point Mutation

Abstract Introduction KRAS was one of the earliest human oncogenes to be described and is one of the most commonly mutated genes in different human cancers, including colorectal cancer. Despite KRAS mutants being known driver mutations, KRAS has proved difficult to target therapeutically, necessitating a comprehensive understanding of the molecular mechanisms underlying KRAS-driven cellular transformation. Objectives To investigate the metabolic signatures associated with single copy mutant KRAS in isogenic human colorectal cancer cells and to determine what metabolic pathways are affected. Methods Using NMR-based metabonomics, we compared wildtype (WT)-KRAS and mutant KRAS effects on cancer cell metabolism using metabolic profiling of the parental KRASG13D/+ HCT116 cell line and its isogenic, derivative cell lines KRAS+/– and KRASG13D/–. Results Mutation in the KRAS oncogene leads to a general metabolic remodelling to sustain growth and counter stress, including alterations in the metabolism of amino acids and enhanced glutathione biosynthesis. Additionally, we show that KRASG13D/+ and KRASG13D/− cells have a distinct metabolic profile characterized by dysregulation of TCA cycle, up-regulation of glycolysis and glutathione metabolism pathway as well as increased glutamine uptake and acetate utilization. Conclusions Our study showed the effect of a single point mutation in one KRAS allele and KRAS allele loss in an isogenic genetic background, hence avoiding confounding genetic factors. Metabolic differences among different KRAS mutations might play a role in their different responses to anticancer treatments and hence could be exploited as novel metabolic vulnerabilities to develop more effective therapies against oncogenic KRAS. Graphical abstract

scholarly journals Molecular subtype-specific responses of colon cancer cells to the SMAC mimetic Birinapant

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Michael Fichtner ◽  
Emir Bozkurt ◽  
Manuela Salvucci ◽  
Christopher McCann ◽  
Katherine A. McAllister ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Caspase 8 ◽  
Colon Cancer Cells ◽  
Apoptosis Pathway ◽  
Iap Antagonist

AbstractColorectal cancer is a molecularly heterogeneous disease. Responses to genotoxic chemotherapy in the adjuvant or palliative setting vary greatly between patients, and colorectal cancer cells often resist chemotherapy by evading apoptosis. Antagonists of an inhibitor of apoptosis proteins (IAPs) can restore defective apoptosis signaling by degrading cIAP1 and cIAP2 proteins and by inhibition of XIAP. Due to the multiple molecular mechanisms-of-action of these targets, responses to IAP antagonist may differ between molecularly distinct colon cancer cells. In this study, responses to the IAP antagonist Birinapant and oxaliplatin/5-fluorouracil (5-FU) were investigated in 14 colon cancer cell lines, representing the consensus molecular subtypes (CMS). Treatment with Birinapant alone did not result in a substantial increase in apoptotic cells in this cell line panel. Annexin-V/PI assays quantified by flow cytometry and high-content screening showed that Birinapant increased responses of CMS1 and partially CMS3 cell lines to oxaliplatin/5-FU, whereas CMS2 cells were not effectively sensitized. FRET-based imaging of caspase-8 and -3 activation validated these differences at the single-cell level, with CMS1 cells displaying sustained activation of caspase-8-like activity during Birinapant and oxaliplatin/5-FU co-treatment, ultimately activating the intrinsic mitochondrial apoptosis pathway. In CMS2 cell lines, Birinapant exhibited synergistic effects in combination with TNFα, suggesting that Birinapant can restore extrinsic apoptosis signaling in the context of inflammatory signals in this subtype. To explore this further, we co-cultured CMS2 and CMS1 colon cancer cells with peripheral blood mononuclear cells. We observed increased cell death during Birinapant single treatment in these co-cultures, which was abrogated by anti-TNFα-neutralizing antibodies. Collectively, our study demonstrates that IAP inhibition is a promising modulator of response to oxaliplatin/5-FU in colorectal cancers of the CMS1 subtype, and may show promise as in the CMS2 subtype, suggesting that molecular subtyping may aid as a patient stratification tool for IAP antagonists in this disease.

scholarly journals Metabolic Profiling of Human Gastric Cancer Cells Treated With Salazosulfapyridine

2020 ◽  
Vol 19 ◽  
pp. 153303382092862
Author(s):  
Kohei Takizawa ◽  
Koji Muramatsu ◽  
Kouji Maruyama ◽  
Kenichi Urakami ◽  
Takashi Sugino ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Nicotinamide Adenine Dinucleotide ◽  
Hct116 Cell ◽  
Combined Treatment ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Nicotinamide Adenine ◽  
Glutathione Metabolism ◽  
Human Gastric Cancer

Purpose: The adhesion molecule cluster of differentiation 44v9 interacts with and stabilizes the cystine/glutamate exchanger protein, which functions as a transporter of cystine. Stabilized cystine/glutamate exchanger increases extracellular cystine uptake and enhances glutathione production. Augmented levels of reduced glutathione mitigate reactive oxygen species and protect cancer cells from apoptosis. Salazosulfapyridine blocks cystine/glutamate exchanger activity and mitigates the supply of cystine to increase intracellular ROS production, thereby increasing cell susceptibility to apoptosis. This enhances the effect of anticancer drugs such as cisplatin. Currently, salazosulfapyridine is being developed as a promising anticancer agent. In the present study, we elucidated the molecular mechanism associated with salazosulfapyridine by investigating the salazosulfapyridine-induced changes in glutathione metabolism in cultured gastric cancer cell lines. Methods: The effect of salazosulfapyridine treatment on glutathione metabolism was investigated in 4 gastric cancer (AGS, MKN1, MKN45, and MKN74) and 2 colorectal cancer (HCT15 and HCT116) cell lines using metabolomic analyses. In addition, the effect of inhibition of the reduced form of nicotinamide adenine dinucleotide phosphate by 2-deoxyglucose on glutathione metabolism was evaluated. Results: Under hypoxia, enhanced glycolysis resulted in lactate accumulation with an associated reduction in nicotinamide adenine dinucleotide phosphate. Salazosulfapyridine treatment decreased the cysteine content and inhibited the formation of glutathione. Combined treatment with salazosulfapyridine and 2-deoxyglucose significantly inhibited cell proliferation. 2-Deoxyglucose, an inhibitor of glycolysis, depleted nicotinamide adenine dinucleotide phosphate required for the formation of glutathione. Conclusions: Our results indicate that in cancer cells having a predominant glycolytic pathway, metabolomic analyses under hypoxic conditions enable the profiling of global metabolism. In addition, inhibiting the supply of nicotinamide adenine dinucleotide phosphate by blocking glycolysis is a potential treatment strategy for cancer, in addition to cystine blockade by salazosulfapyridine.

scholarly journals Localization of the Kinesin-like Protein Xklp2 to Spindle Poles Requires a Leucine Zipper, a Microtubule-associated Protein, and Dynein

1998 ◽  
Vol 143 (3) ◽  
pp. 673-685 ◽  
Author(s):  
Torsten Wittmann ◽  
Haralabia Boleti ◽  
Claude Antony ◽  
Eric Karsenti ◽  
Isabelle Vernos
Keyword(s):  
Leucine Zipper ◽  
Molecular Mechanisms ◽  
Single Point ◽  
Spindle Pole ◽  
Single Point Mutation ◽  
Spindle Poles ◽  
Centrosome Separation ◽  
Egg Extracts ◽  
Xenopus Egg ◽  
Xenopus Egg Extracts

Xklp2 is a plus end–directed Xenopus kinesin-like protein localized at spindle poles and required for centrosome separation during spindle assembly in Xenopus egg extracts. A glutathione-S-transferase fusion protein containing the COOH-terminal domain of Xklp2 (GST-Xklp2-Tail) was previously found to localize to spindle poles (Boleti, H., E. Karsenti, and I. Vernos. 1996. Cell. 84:49–59). Now, we have examined the mechanism of localization of GST-Xklp2-Tail. Immunofluorescence and electron microscopy showed that Xklp2 and GST-Xklp2-Tail localize specifically to the minus ends of spindle pole and aster microtubules in mitotic, but not in interphase, Xenopus egg extracts. We found that dimerization and a COOH-terminal leucine zipper are required for this localization: a single point mutation in the leucine zipper prevented targeting. The mechanism of localization is complex and two additional factors in mitotic egg extracts are required for the targeting of GST-Xklp2-Tail to microtubule minus ends: (a) a novel 100-kD microtubule-associated protein that we named TPX2 (Targeting protein for Xklp2) that mediates the binding of GST-Xklp2-Tail to microtubules and (b) the dynein–dynactin complex that is required for the accumulation of GST-Xklp2-Tail at microtubule minus ends. We propose two molecular mechanisms that could account for the localization of Xklp2 to microtubule minus ends.

scholarly journals TCN1 Deficiency Inhibits The Malignancy of Colorectal Cancer Cells By Regulating The ITGB4 Pathway

2021 ◽  
Author(s):  
Xinqiang Zhu ◽  
Xuetong Jiang ◽  
Qinglin Zhang ◽  
Hailong Huang ◽  
Xiaohong Shi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Function Analysis ◽  
Hct116 Cell ◽  
Tumor Xenograft ◽  
Integrin Subunit ◽  
Filamin A ◽  
Loss Of Function ◽  
Colorectal Cancer Cells

Abstract Background: This study aimed to investigate the biological function and regulatory mechanism of TCN1 in colorectal cancer (CRC). Methods: We studied the biological functions of TCN1 using gain-of-function and loss-of-function analysis in HCT116 cell lines, and examined the effects of TCN1 on the proliferation, apoptosis, and invasion of CRC cells and determined its potential molecular mechanisms using CRC lines and mouse xenotransplantation models. Tumor xenograft and tumor metastasis studies were performed to detect the tumorigenicity and metastasis of cells in vivo. Results: TCN1-knockdown attenuated CRC cell proliferation, invasion and promoted cell apoptosis. Overexpression of TCN1 yielded the opposite effects. In addition, TCN1-knockdown HCT116 cells failed to form metastatic foci in the peritoneum after intravenous injection. Molecular mechanism studies showed that TCN1 interacts with integrin subunit β4 (ITGB4) to positively regulate the expression of ITGB4. TCN1-knockdown promoted the degradation of ITGB4 and increased the instability of ITGB4 and filamin A (FLNA). Downregulation of ITGB4 at the protein level resulted in the disassociation of the ITGB4/PLEC complex, leading to cytoskeletal damage. Conclusion: TCN1 might exert oncogenic role in CRC via regulating the ITGB4 signaling pathway.

scholarly journals Divergent Actions of Pyruvate and ATP in Glucose-mediated Irinotecan Chemoresistance in Colorectal Cancer

2021 ◽  
Author(s):  
Chung-Yen Huang ◽  
Yu-Chen Pai ◽  
Linda Chia-Hui Yu
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
High Glucose ◽  
Structural Damage ◽  
Topoisomerase I ◽  
Molecular Mechanisms ◽  
Flow Cytometric Analysis ◽  
Quiescent State ◽  
Altered Glucose ◽  
Induced Apoptosis

Abstract Background: Altered glucose metabolism is associated with chemoresistance in colorectal cancer (CRC). The aim of this study was to illustrate the molecular mechanisms of glucose-mediated chemoresistance against irinotecan, a topoisomerase I inhibitor, focusing on the distinct roles of metabolites such as pyruvate and ATP in modulating cell death and proliferation. Methods: Four human CRC cell lines, tumorspheres, and mouse xenograft models were treated with various doses of irinotecan in the presence of high concentrations of glucose, pyruvate or ATP-encapsulated liposomes. Cell apoptosis was measured by DNA fragmentation and caspase activities, and necroptosis was evaluated by immunoprecipitation of receptor-interacting protein kinase (RIP) 1/3 complex. Cell cycles were assessed by flow cytometric analysis.Results: Human CRC cell lines treated with irinotecan in the presence of high glucose displayed increased cell viability and larger xenograft tumor sizes in mouse models compared to those treated in the presence of normal glucose. Irinotecan induced apoptosis and necroptosis, both of which were mitigated by high glucose. Liposomal ATP prevented irinotecan-induced apoptosis, while it had no effect on necroptosis. In contrast, pyruvate attenuated the RIP1/3-dependent necroptosis via free radical scavenging, without modulating apoptotic levels. Regarding the cell cycle, liposomal ATP aggravated irinotecan-induced G0/G1 shift whereas pyruvate diminished the G0/G1 shift, showing opposite effects on proliferation. Last, tumorsphere structural damage, an index of solid tumor responsiveness to chemotherapy, was determined. Liposomal ATP increased tumorsphere sizes while pyruvate prevented the deformation of spheroid mass. Conclusions: Glucose metabolites confer tumor chemoresistance via multiple modes of action. Glycolytic pyruvate attenuated irinotecan-induced necroptosis and potentiated drug insensitivity by shifting cells from a proliferative to quiescent state. On the other hand, ATP decreased irinotecan-induced apoptosis and promoted active cell proliferation, which might contribute to tumor recurrence.

scholarly journals Tumour-Derived Cell Lines and Their Potential for Therapy Prediction in Patients with Metastatic Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4717
Author(s):  
Sandra Wagner ◽  
Nicola T. Beger ◽  
Stephanie Matschos ◽  
Antonia Szymanski ◽  
Randy Przybylla ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Treatment Response ◽  
Cell Lines ◽  
Primary Tumour ◽  
Clinical Treatment ◽  
Driver Mutations ◽  
Cell Models ◽  
Good Tool

The prognosis of metastatic colorectal cancer (CRC) remains poor. Patients and physicians are in need of individual therapies and precise response predictions. We investigated the predictive capacity of primary tumour material for treatment response of metastases. Mutational landscapes of primary tumours and corresponding metastases of 10 CRC patients were compared. Cell line characteristics and chemosensitivity were investigated pairwise for primary and metastatic tumours of four patients. PDX models of one patient were treated in vivo for proof of concept. Driver mutations did not differ between primaries and metastases, while the latter accumulated additional mutations. In vitro chemosensitivity testing revealed no differences for responses to 5-FU and oxaliplatin between primary and metastatic cell lines. However, irinotecan response differed significantly: the majority of metastases-derived cell lines was less sensitive to irinotecan than their matching primary counterpart. Therapy recommendations based on these findings were compared to clinical treatment response and mostly in line with the predicted outcome. Therefore, primary tumour cell models seem to be a good tool for drug response testing and conclusion drawing for later metastases. With further data from tumour-derived cell models, such predictions could improve clinical treatment decisions, both recommending likely effective therapeutic options while excluding ineffective treatments.

scholarly journals Regulation of lnc-TLCD2-1 on Radiation Sensitivity of Colorectal Cancer and Comprehensive Analysis of Its Mechanism

2021 ◽  
Vol 11 ◽  
Author(s):  
Qifeng Yu ◽  
Wei Zhang ◽  
Xin Zhou ◽  
Wenqi Shen ◽  
Chungen Xing ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Radiation Resistance ◽  
Radiation Treatment ◽  
Cell Clone ◽  
Hct116 Cell ◽  
Radiation Sensitivity ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Control Group

As is well known that colorectal cancer is the third most common cancer in the world, and radiation treatment plays a vital role in colorectal cancer therapy, but radiation resistance is a significant problem in the treatment of colorectal cancer. As an important member of the non-coding RNA family, long non-coding RNAs (lncRNAs) have been found that it plays a role in the occurrence and progression of colorectal cancer in recent years. However, little is known about the effect of lncRNA on colorectal cancer sensitivity to radiotherapy. We found that lnc-TLCD2-1 was significantly differentially expressed in radiation-tolerant CCL244 cell lines and radiation-sensitive HCT116 cell lines, suggesting that lnc-TLCD2-1 may regulate the radiosensitivity of colorectal cancer, and the relevant underlying mechanism was investigated. Cell clone formation assay, flow cytometry, and cell counting kit 8 (CCK8) were used to detect radiation sensitivity, apoptosis, and proliferation of colorectal cancer cells, respectively; Quantitative real-time PCR and western blot were used to detect the expression of genes; the direct interaction between lnc-TLCD2-1 and hsa-miR-193a-5p was verified by dual luciferase reporter assays; GEPIA, Starbase, TIMER and DAVID were used to complete expression of lnc-TLCD2-1, miR-193a-5p,YY1 and NF-кB-P65 in colorectal cancer, correlation, immune cell infiltration, GO and KEGG enrichment analysis. Clinical prognostic analysis data were obtained from GSE17536 dataset. After radiotherapy for HCT116, the expression of lnc-TLCD2-1 was increased, and the expression of hsa-miR-193a-5p was significantly decreased, while that of CCL244 was the opposite, and the change range of lnc-TLCD2-1 was relatively small. HCT116 with overexpression of lnc-TLCD2-1 after radiation treatment, the number of cell colonies significantly increased, and cell apoptosis decreased compared with the negative control group. The cell colonies and apoptosis of CCL244 with disturbed expression of lnc-TLCD2-1 were opposite to those of HCT116. Lnc-TLCD2-1 can regulate the expression of YY1/NF-кB-P65 by targeting miR-193a-5p. Lnc-TLCD2-1 can promote the proliferation of colorectal cancer. High expression of lnc-TLCD2-1 independently predicted a shorter survival. Lnc-TLCD2-1 is associated with radiation resistance and short survival in colorectal cancer patients. In addition, Lnc-TLCD2-1 can promote the proliferation of colorectal cancer. Our study provides a scientific basis for targeting lnc-TLCD2-1 in colorectal cancer radiation resistance interventions and selection of prognostic biomarker.

scholarly journals LOXL1 modulates the malignant progression of colorectal cancer by inhibiting the transcriptional activity of YAP

2020 ◽  
Author(s):  
Lin Hu ◽  
Jing Wang ◽  
Yunliang Wang ◽  
Linpeng Wu ◽  
Chao Wu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Cancer Progression ◽  
Colony Formation ◽  
Transcriptional Activity ◽  
Tumour Growth ◽  
Molecular Mechanisms ◽  
Migration And Invasion

Abstract Background: LOX-like 1 (LOXL1) is a lysyl oxidase, and emerging evidence has revealed its effect on malignant cancer progression. However, its role in colorectal cancer (CRC) and the underlying molecular mechanisms have not yet been elucidated. Methods: LOXL1 expression in colorectal cancer was detected by immunohistochemistry, western blotting and real-time PCR. In vitro , colony formation, wound healing, migration and invasion assays were performed to investigate the effects of LOXL1 on cell proliferation, migration and invasion. In vivo , metastasis models and mouse xenografts were used to assess tumorigenicity and metastasis ability. Molecular biology experiments were utilized to reveal the underlying mechanisms by which LOXL1 modulates the Hippo pathway. Results: LOXL1 was highly expressed in normal colon tissues compared with cancer tissues. In vitro, silencing LOXL1 in CRC cell lines dramatically enhanced migration, invasion, and colony formation, while overexpression of LOXL1 exerted the opposite effects. The results of the in vivo experiments demonstrated that the overexpression of LOXL1 in CRC cell lines drastically inhibited metastatic progression and tumour growth. Mechanistically, LOXL1 inhibited the transcriptional activity of Yes-associated protein (YAP) by interacting with MST1/2 and increasing the phosphorylation of MST1/2. Conclusions: LOXL1 may function as an important tumour suppressor in regulating tumour growth, invasion and metastasis via negative regulation of YAP activity.

scholarly journals LOXL1 modulates the malignant progression of colorectal cancer by inhibiting the transcriptional activity of YAP

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Lin Hu ◽  
Jing Wang ◽  
Yunliang Wang ◽  
Linpeng Wu ◽  
Chao Wu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Cancer Progression ◽  
Colony Formation ◽  
Transcriptional Activity ◽  
Tumour Growth ◽  
Molecular Mechanisms ◽  
Migration And Invasion

Abstract Background LOX-like 1 (LOXL1) is a lysyl oxidase, and emerging evidence has revealed its effect on malignant cancer progression. However, its role in colorectal cancer (CRC) and the underlying molecular mechanisms have not yet been elucidated. Methods LOXL1 expression in colorectal cancer was detected by immunohistochemistry, western blotting and real-time PCR. In vitro, colony formation, wound healing, migration and invasion assays were performed to investigate the effects of LOXL1 on cell proliferation, migration and invasion. In vivo, metastasis models and mouse xenografts were used to assess tumorigenicity and metastasis ability. Molecular biology experiments were utilized to reveal the underlying mechanisms by which LOXL1 modulates the Hippo pathway. Results LOXL1 was highly expressed in normal colon tissues compared with cancer tissues. In vitro, silencing LOXL1 in CRC cell lines dramatically enhanced migration, invasion, and colony formation, while overexpression of LOXL1 exerted the opposite effects. The results of the in vivo experiments demonstrated that the overexpression of LOXL1 in CRC cell lines drastically inhibited metastatic progression and tumour growth. Mechanistically, LOXL1 inhibited the transcriptional activity of Yes-associated protein (YAP) by interacting with MST1/2 and increasing the phosphorylation of MST1/2. Conclusions LOXL1 may function as an important tumour suppressor in regulating tumour growth, invasion and metastasis via negative regulation of YAP activity. Graphical abstract

scholarly journals Molecular mechanisms of activated protein C resistance. Properties of factor V isolated from an individual with homozygosity for the Arg506 to Gln mutation in the factor V gene

1996 ◽  
Vol 313 (2) ◽  
pp. 467-472 ◽  
Author(s):  
Cristina APARICIO ◽  
Björn DAHLBÄCK
Keyword(s):  
Risk Factor ◽  
Protein C ◽  
Molecular Mechanisms ◽  
Single Point ◽  
Activated Protein C ◽  
Factor Xa ◽  
Single Point Mutation ◽  
Factor V ◽  
Apc Resistance ◽  
Anticoagulant System

Resistance to activated protein C (APC), which is the most prevalent pathogenetic risk factor of thrombosis, is linked to a single point-mutation in the factor V (FV) gene, which predicts replacement of Arg (R) at position 506 with a Gln (Q). This mutation modifies one of three APC-cleavage sites in the heavy chain of activated FV (FVa), suggesting that mutated FVa (FVa:Q506) is at least partially resistant to APC-mediated degradation. To elucidate the molecular mechanisms of APC-resistance and to investigate the functional properties of FV in APC resistance, FV:Q506 was purified from an individual with homozygosity for the Arg to Gln mutation. Intact and activated FV:Q506 were demonstrated to convey APC resistance to FV-deficient plasma. Thrombin- or factor Xa-activated FV:Q506 were found to be approx. 10-fold less sensitive to APC-mediated degradation than normal FVa, at both high and low phospholipid concentrations. The degradation pattern observed on Western blotting suggested that FVa:Q506 was not cleaved at position 506. However, it was slowly cleaved at Arg306, which explains the partial APC sensitivity of FVa:Q506. FV is initially activated during clotting and then rapidly inactivated in a process which depends on the integrity of the protein C anticoagulant system. During clotting of APC-resistant plasma, FV:Q506 was activated in a normal fashion, but then only partially inactivated. In conclusion, the reduced sensitivity of FVa:Q506 to APC-mediated degradation is the molecular basis for the life-long hypercoagulable state which constitutes a risk factor for thrombosis in APC-resistant individuals.

Sign in / Sign up

Export Citation Format

Share Document