Stimulus-induced expression of the ABCG2 multidrug transporter in HepG2 hepatocarcinoma model cells involves the ERK1/2 cascade and alternative promoters

Boussac, Hugues de; Orbán, Tamás I.; Várady, György; Tihanyi, Borbála; Bacquet, Caroline; Brózik, Anna; Váradi, András; Sarkadi, Balázs; Arányi, Tamàs

doi:10.1016/j.bbrc.2012.08.046

Cited by 16 publications

(11 citation statements)

References 26 publications

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“…1). These findings were in line with earlier observations on stem cells [18,38], and in agreement with the results of Nakanishi et al [25] describing the expression of variant E1A in the parental MCF-7, and in a higher level, in the MCF-7/AdrVp selected cell line. In previous studies, however, variant E1U could not be detected even in drug selected cell lines [25], and was found to be expressed only in cells of hematopoietic origin, namely in dendritic cells [18], the CHRF megakaryoblast cell line [18] and in a subtype of pediatric acute megakaryoblastic leukemia [27].…”

Section: Possible Upstream Alternative Translation Regulations: the Psupporting

confidence: 93%

“…Here we show that MCF-7 cells treated with certain drugs (such as flavopiridol) also express the E1U variant (Fig. 1), presumably due to the modulation of specific pathways by the drug, and affecting different promoter regions, as suggested by our previous studies [38].…”

Section: Possible Upstream Alternative Translation Regulations: the Psupporting

confidence: 79%

“…The fact that such variance in the 5' UTR region is conserved between the mouse and the human ABCG2 suggests an evolutionary conserved role, yet little is known about the potential function(s) of these splice variants. Previous studies mainly focused on transcriptional regulation by investigating transcription factor binding sites in promoters [37][38][39][40][41][42], and little attention was paid to the mRNA isoforms produced by such alternative transcription events.…”

Section: Possible Upstream Alternative Translation Regulations: the Pmentioning

confidence: 99%

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Functional characterization of the ABCG2 5′ non-coding exon variants: Stem cell specificity, translation efficiency and the influence of drug selection

Sándor

Jordanidisz

Schamberger

et al. 2016

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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Functional characterization of the ABCG2 5' non-coding exon variants: stem cell specificity, translation efficiency and the influence of drug selection, BBA -Gene Regulatory Mechanisms (2016Mechanisms ( ), doi: 10.1016Mechanisms ( /j.bbagrm.2016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT2 Abstract ABCG2 is a multidrug transporter with wide substrate specificity, and is believed to protect several cell types from various xenobiotics and endobiotics. This "guardian" function is important in numerous cell types and tissue barriers but becomes disadvantageous by being responsible for the multidrug resistance phenotype in certain tumor cells. ABCG2 regulation at the protein level has already been extensively studied, however, regulation at the mRNA level, especially the functional role of the various 5' untranslated exon variants (5' UTRs) has been elusive. In the present work, we describe a comprehensive characterization of four ABCG2 mRNA variants with different exon 1 sequences, investigate drug inducibility, stem cell specificity, mRNA stability, and translation efficiency. Although certain variants (E1B and E1C) are considered as "constitutive" mRNA isoforms, we show that chemotoxic drugs significantly alter the expression pattern of distinct ABCG2 mRNA isoforms. When examining human embryonic stem cell lines, we provide evidence that variant E1A has an expression pattern coupled to undifferentiated stem cell stage, as its transcript level is regulated parallel to mRNAs of Oct4 and Nanog pluripotency marker genes. When characterizing the four exon 1 variants we found no significant differences in terms of mRNA stabilities and half-lives of the isoforms. In contrast, variant E1U showed markedly lower translation efficiency both at the total protein level or regarding the functional presence in the plasma membrane. Taken together, these results indicate that the different 5' UTR variants play an important role in cell type specific regulation and fine tuning of ABCG2 expression.

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Section: Possible Upstream Alternative Translation Regulations: the Psupporting

confidence: 93%

Section: Possible Upstream Alternative Translation Regulations: the Psupporting

confidence: 79%

Section: Possible Upstream Alternative Translation Regulations: the Pmentioning

confidence: 99%

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Functional characterization of the ABCG2 5′ non-coding exon variants: Stem cell specificity, translation efficiency and the influence of drug selection

Sándor

Jordanidisz

Schamberger

et al. 2016

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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“…ABCG2 transporter protein is one of the most important ABC ubiquitously expressed in different tissues and contributes to the disposition of a wide variety of endogenous substances including platinum-based regimens [19,20] and cholesterol [21]. Recent studies reported an association of ABCG2 expression with the prognosis and survival of cancer patients [22e24].…”

Section: Discussionmentioning

confidence: 99%

Cholesterol reduces the sensitivity to platinum-based chemotherapy via upregulating ABCG2 in lung adenocarcinoma

Tang

et al. 2015

Biochemical and Biophysical Research Communications

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“…Recent studies suggest that fibroblast secreted factors influence expression of drug transporter proteins in cancer cells. Liver cancer cells have been shown to induce HGF expression in CAFs, which in turn act on cancer cells to enhance expression of drug transporter proteins BCRP and MRP1 (de Boussac et al, 2012). These studies indicate that the fibroblast niche potentially regulates multi-drug resistance through drug efflux mechanisms; however, further studies must be performed to validate these mechanisms.…”

Section: Concluding Remarks/future Directionsmentioning

confidence: 99%

Priming cancer cells for drug resistance: role of the fibroblast niche

2014

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Conventional and targeted chemotherapies remain integral strategies to treat solid tumors. Despite the large number of anti-cancer drugs available, chemotherapy does not completely eradicate disease. Disease recurrence and the growth of drug resistant tumors remain significant problems in anti-cancer treatment. To develop more effective treatment strategies, it is important to understand the underlying cellular and molecular mechanisms of drug resistance. It is generally accepted that cancer cells do not function alone, but evolve through interactions with the surrounding tumor microenvironment. As key cellular components of the tumor microenvironment, fibroblasts regulate the growth and progression of many solid tumors. Emerging studies demonstrate that fibroblasts secrete a multitude of factors that enable cancer cells to become drug resistant. This review will explore how fibroblast secretion of soluble factors act on cancer cells to enhance cancer cell survival and cancer stem cell renewal, contributing to the development of drug resistant cancer.

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Stimulus-induced expression of the ABCG2 multidrug transporter in HepG2 hepatocarcinoma model cells involves the ERK1/2 cascade and alternative promoters

Cited by 16 publications

References 26 publications

Functional characterization of the ABCG2 5′ non-coding exon variants: Stem cell specificity, translation efficiency and the influence of drug selection

Functional characterization of the ABCG2 5′ non-coding exon variants: Stem cell specificity, translation efficiency and the influence of drug selection

Cholesterol reduces the sensitivity to platinum-based chemotherapy via upregulating ABCG2 in lung adenocarcinoma

Priming cancer cells for drug resistance: role of the fibroblast niche

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