Abstract
The present study of inhibitors shows that the histone deacetylase-induced increase in P-glycoprotein (Pgp) mRNA (MDR1 mRNA) does not parallel either an increase in Pgp protein or an increase in Pgp activity in several colon carcinoma cell lines. Furthermore, studying the polysome profile distribution, we show a translational control of Pgp in these cell lines. In addition, we show that the MDR1 mRNA produced in these cell lines is shorter in its 5' end that the MDR1 mRNA produced in the MCF-7/Adr (human breast carcinoma) and K562/Adr (human erythroleukemia) cell lines, both of them expressing Pgp. The different size of the MDR1 mRNA is due to the use of alternative promoters. Our data suggest that the translational blockade of MDR1 mRNA in the colon carcinoma cell lines and in wild-type K562 cells could be overcome by alterations in the 5' end of the MDR1 mRNA in the resistant variant of these cell lines, as in the case of the K562/Adr cell line. This is, to our knowledge, the first report demonstrating that the presence of an additional 5' untranslated fragment in the MDR1 mRNA improves the translational efficiency of this mRNA.
Highlights
Multidrug resistance (MDR) constitutes a major obstacle for the success of cancer treatment
To determine whether the trichostatin A (TSA)-induced increase in MDR1 mRNA expression observed in the human colon carcinoma cell line SW620 [17] was a specific phenomenon related to a particular cell line or it constitutes a more general phenomenon, we have determined the level of MDR1 mRNA in SW620, HT-29, and HT-29/M6 human colon carcinoma cell lines in the presence and absence of TSA
We found that independent of the observed increase in MDR1 mRNA, TSA and suberoylanilide hydroxamic acid (SAHA) were able to induce apoptosis in these cell lines, as shown by the presence of a sub-G1 peak determined by flow cytometry analysis after treatment with iHDACs (Fig. 1B and Supplementary Fig. S1)
Summary
Multidrug resistance (MDR) constitutes a major obstacle for the success of cancer treatment. Several mechanisms could be involved in the acquisition of this phenotype, the role of two different membrane proteins, P-glycoprotein (Pgp) and MDR-associated protein (MRP), has been well established [2,3,4]. Both proteins are members of the same ATP-binding cassette superfamily of transport proteins. In addition to its role during the acquisition of the MDR phenotype, Pgp is expressed in normal tissues, both as a consequence of differentiation and in response to environmental challenges, and it has been proposed to play a role as a cell protector against cellular toxins [5]. It is clear that Pgp shows several functions in different cells and tissues
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