MDR1/P-glycoprotein expression in colorectal cancer

Linn, S. C.; Giaccone, Giuseppe

doi:10.1016/0959-8049(95)00278-q

Cited by 60 publications

(36 citation statements)

References 22 publications

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“…An increased expression of ABCB1 has been demonstrated in colorectal carcinomas [277,278]. Moreover, increased expression of -catenin and ABCB1 was also detected in carcinoma tissues of patients with FAP [78].…”

Section: Activation Of the -Catenin/tcf4 Signaling Cascade: A Triggermentioning

confidence: 99%

The Role of Wnt/Beta-Catenin Signaling in Renal Carcinogenesis: Lessons from Cadmium Toxicity Studies

Thévenod¹,

Chakraborty

2010

CMM

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Wnt/beta-catenin signaling plays a crucial role during embryogenesis. However, this signaling pathway also plays a role in normal adult tissues and in carcinogenesis, including cadmium (Cd2+) induced nephrocarcinogenesis, which is the topic of this review. Wnt/beta-catenin signaling is tightly regulated in mature epithelia to balance cell proliferation, differentiation and death. This is accomplished by modulating phosphorylation of the multifunctional protein beta-catenin which in turn determines its preference for a particular fate, i.e. cell-cell adhesion by binding to E-cadherin, proteasomal degradation, or co-activation of the transcription factor Tcf/Lef. The pivotal role of beta-catenin is not limited to Wnt signaling, but can be challenged by other transcription factors under stress conditions (e.g. FOXO, HIF-1alpha, NF-kappaB, c-jun), where beta-catenin acts as a molecular switch in response to the cellular redox status. Aberrant Wnt/beta-catenin signaling can contribute to carcinogenesis of intestinal, lung or kidney epithelia, either by mutations of its signaling components and/or disruption of linked signaling networks. The nephrotoxic metal Cd2+ causes renal cancer in humans. Because it is not genotoxic Cd2+ is thought to induce mutations and carcinomas indirectly: Possible mechanisms include oxidative stress, inhibition of DNA repair, aberrant gene expression, deregulation of cell proliferation, resistance to apoptosis, and/or disruption of cell adhesion. Wnt signaling may contribute to Cd2+ carcinogenesis because Cd2+ disrupts the junctional E-cadherin/beta-catenin complex, resulting in excessive nuclear translocation of beta-catenin and activation of Tcf4. Up-regulation of target genes of the beta-catenin/Tcf4 complex, such as c-myc, cyclin D1 and the multidrug transporter P-glycoprotein (MDR1/ABCB1), leads to increased proliferation, evasion of apoptosis, adaptation to Cd2+ toxicity and thereby promotes the selection of mutated and pre-neoplastic cells.

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Section: Activation Of the -Catenin/tcf4 Signaling Cascade: A Triggermentioning

confidence: 99%

The Role of Wnt/Beta-Catenin Signaling in Renal Carcinogenesis: Lessons from Cadmium Toxicity Studies

Thévenod¹,

Chakraborty

2010

CMM

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“…Loss of E cadherin protein occurs in several cancers, including colorectal cancer, and is associated with the development of invasive properties. [75][76][77] Other proteins that may be associated with invasion of colorectal cancers include those involved in tissue degradation, such as urokinase plasminogen activators and matrix metalloproteinases/ collagenases. 78 79 The cells of metastases may have genotypes and/or patterns of gene expression distinct from primary tumours.…”

Section: Malignancymentioning

confidence: 99%

What we could do now: molecular pathology of colorectal cancer

Houlston

2001

Molecular Pathology

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The contribution of molecular genetics to colorectal cancer has been largely restricted to relatively rare inherited tumours and to the detection of germ line mutations predisposing to these cancers. However, much is now known about the somatic events leading to colorectal cancer in general. Several studies have examined the relation between genetic features and prognosis. The purpose of this article is to review these studies and summarise the current state of this subject. Although many of the published studies are small and inconclusive, it is clear that several diVerent pathways exist for the development of this cancer, and some molecular characteristics seem to correlate with clinicopathological features. At present, studies are confined to evaluating a small number of molecular markers; however, with the advent of methods for the rapid genetic profiling of large numbers of colorectal cancers, it will be possible to evaluate fully the clinical usefulness of a range of colorectal cancer genotypes. (J Clin Pathol: Mol Pathol 2001;54:206-214)

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“…Mdr-1 gene expression is controled by several mechanisms including action of transcription factors such as YB-1, c-Jun/c-fos, AP-1 and also by DNA methylation [5]. Mdr-1 promoter methylation was shown to be also related to cancer invasiveness [6] and to cancer cell proliferation [7]. However, there are still no clear clues about the mechanisms triggering mdr-1 gene overexpression in cancer.…”

Section: Introductionmentioning

confidence: 99%

Cobalamin Potentiates Vinblastine Cytotoxicity Through Downregulation of mdr-1 Gene Expression in HepG2 Cells

Marguerite¹,

Béri-Dexheimer²,

Ortiou³

et al. 2007

Cell Physiol Biochem

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Background: P-glycoprotein (Pgp), produced by multidrug resistance-1 gene (mdr-1), is a main mechanism developed by cancer cells to guard against anti-cancer drugs. Alterations of DNA methylation of the mdr-1 gene promoter are known to be linked to mdr-1 gene expression and are probably related to intracellular S-adenosyl-methionine. We here used HepG2 cells to determine the role of the methionine cycle (through the use of the Methionine-Synthase (MS) cofactor, cobalamin) on mdr-1 gene expression. Methods: Semiquantitative RT-PCR of mdr-1 gene, cellular retention of rhodamine-123, and vinblastine cytotoxicity were carried out on cells cultivated with and without cobalamin. Methylation status of the mdr-1 gene promoter was determined by methylation-specific PCR. Results: Addition of cobalamin to the cells led to an increase in MS activity, to a significant decrease in mdr-1 gene expression which is correlated to an increase in retention of the Pgp substrate Rhodamine 123. Furthermore, cobalamin potentiated cell sensitivity to vinblastine to the same range as that of the Pgp blocker verapamil and prevented methotrexate-induced up-regulation of mdr-1 gene expression. However, no modification in methylation of the mdr-1 gene promoter was observed. Conclusion: Cobalamin downregulates mdr-1 gene expression, as well as Pgp expression and function, and significantly increases cytotoxicity of vinblastine. The identification of this novel way of diminishing cellular resistance to the chemotherapeutic agent vinblastine holds promises of leading to better treatments for cancer patients.

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MDR1/P-glycoprotein expression in colorectal cancer

Cited by 60 publications

References 22 publications

The Role of Wnt/Beta-Catenin Signaling in Renal Carcinogenesis: Lessons from Cadmium Toxicity Studies

The Role of Wnt/Beta-Catenin Signaling in Renal Carcinogenesis: Lessons from Cadmium Toxicity Studies

What we could do now: molecular pathology of colorectal cancer

Cobalamin Potentiates Vinblastine Cytotoxicity Through Downregulation of mdr-1 Gene Expression in HepG2 Cells

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