Aberrant Transcription from an Unrelated Promoter Can Result in <i>MDR-1</i> Expression following Drug Selection <i>In vitro</i> and in Relapsed Lymphoma Samples

Huff, Lyn M.; Zheng, Wang; Iglesias, Angel; Fojo, Tito; Lee, Jong-Seok

doi:10.1158/0008-5472.can-04-1349

Cited by 24 publications

(11 citation statements)

References 43 publications

(38 reference statements)

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“…Reactivated HERVLE can modulate expression of adjacent genes. For instance, HERVLE have been shown to act as alternate promoters for varying cellular genes in Hodgkin lymphoma and Non-Hodgkin lymphoma cells ( Huff et al, 2005 ; Lamprecht et al, 2010 ; Lock et al, 2014 ; Babaian et al, 2016 ).…”

Section: Endogenous Viral Elements (Eve)mentioning

confidence: 99%

Endogenous Retrovirus 3 – History, Physiology, and Pathology

et al. 2018

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Endogenous viral elements (EVE) seem to be present in all eukaryotic genomes. The composition of EVE varies between different species. The endogenous retrovirus 3 (ERV3) is one of these elements that is present only in humans and other Catarrhini. Conservation of ERV3 in most of the investigated Catarrhini and the expression pattern in normal tissues suggest a putative physiological role of ERV3. On the other hand, ERV3 has been implicated in the pathogenesis of auto-immunity and cancer. In the present review we summarize knowledge about this interesting EVE. We propose the model that expression of ERV3 (and probably other EVE loci) under pathological conditions might be part of a metazoan SOS response.

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Section: Endogenous Viral Elements (Eve)mentioning

confidence: 99%

Endogenous Retrovirus 3 – History, Physiology, and Pathology

et al. 2018

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“…Unexpectedly, these gene hybrids differed, suggesting that ABCB 1 merely required a sufficiently active promoter to activate it and that the specific promoter was irrelevant. Other ABCB 1 mRNA hybrids have also been reported (47). These hybrids were regulated by nearby genomic sequences with similarity to a retroviral element.…”

Section: Mechanisms Of Overexpression In Multi-step Selected Cell Linesmentioning

confidence: 95%

Molecular Mechanisms of Drug Resistance in Single-Step and Multi-Step Drug-Selected Cancer Cells

Calcagno

Ambudkar

2009

Methods in Molecular Biology

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Multidrug resistance (MDR) remains one of the key determinants in chemotherapeutic success of cancer patients. Often, acquired resistance is mediated by the overexpression of ATP-binding cassette (ABC) drug transporters. To study the mechanisms involved in the MDR phenotype, investigators have generated a variety of in vitro cell culture models using both multi-step and single-step drug selections. Sublines produced from multi-step selections have led to the discovery of several crucial drug transporters including ABCB1, ABCC1 and ABCG2. Additionally, a number of mechanisms causing gene overexpression have been elucidated. To more closely mimic in vivo conditions, investigators have also established MDR sublines with single-step drug selections. Here we examine some of the multi-step and single-step selected cell lines generated to elucidate the mechanisms involved in the development of MDR in cancer cells.

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“…Several causes such as intrinsic cancer genomic instability, epigenetic mechanisms and inflammatory stressors in the tumor microenvironment have been implicated to play a critical role in the upregulation of P-gp expression ( Figure 2) (49). Studies have demonstrated that gene rearrangements and tumor mutational burden are important mechanisms to control and modulate promoter region of abcb1 gene leading to its expression (50,51). Oncogenes such as Ras, p53, c-Raf, etc.…”

Section: P-gp: Protein Expression Structure and Functionmentioning

confidence: 99%

Perplexing Role of P-Glycoprotein in Tumor Microenvironment

2020

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Development of multidrug resistance (MDR) still remains a major obstacle to the long-term success of cancer therapy. P-glycoprotein (P-gp) is a well-identified membrane transporter with capability to efflux drug molecules out of the cancer cell leading to reduced efficiency of chemotherapy. Cancer cells upregulate P-gp expression as an adaptive response to evade chemotherapy mediated cell death. While several P-gp inhibitors have been discovered by in silico and pre-clinical studies, very few have successfully passed all phases of the clinical trials. Studies show that application of P-gp inhibitors in cancer therapy regimen following development of MDR achieved limited beneficial outcomes. While, the non-specific substrate binding to P-gp has made the drug-design a challenge, a bigger perplexing challenge comes from its role in tumor immunology. Expression of P-gp was noted immune cell phenotypes with apparently antagonistic functionality. Both pro-tumor M 2-macrophages and, anti-tumor NK-cell and Th17/CD4 + T cell subsets have shown enhanced expression of P-gp. While drug based inhibition of P-gp in pro-tumor immune cell phenotypes could promote tumor elimination, however, it would not be a rational choice to exert inhibition of P-gp on anti-tumor immune cell phenotypes. This mutually exclusive paradigm of P-gp functionality requires a more comprehensive and detailed understanding of its role in tumor microenvironment with active interplay of cancer and immune cells in the tumor mileu. In this review, we focus on the current understanding of the role of P-gp in cancer cells and immune cells and finally attempt to highlight some caveats in the current understanding of its role in comprehensive tumor microenvironment along with challenges in the development of P-gp inhibitors toward anti-cancer therapy.

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Aberrant Transcription from an Unrelated Promoter Can Result in MDR-1 Expression following Drug Selection In vitro and in Relapsed Lymphoma Samples

Abstract: The development of drug resistance in the treatment of cancer remains a major problem.

Cited by 24 publications

References 43 publications

Endogenous Retrovirus 3 – History, Physiology, and Pathology

Endogenous Retrovirus 3 – History, Physiology, and Pathology

Molecular Mechanisms of Drug Resistance in Single-Step and Multi-Step Drug-Selected Cancer Cells

Perplexing Role of P-Glycoprotein in Tumor Microenvironment

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