Post-Transcriptional Controls by Ribonucleoprotein Complexes in the Acquisition of Drug Resistance

Abstract

Acquisition of drug resistance leads to failure of anti-cancer treatments and therapies. Although several successive chemotherapies are available, along with efforts towards clinical applications of new anti-cancer drugs, it is generally realized that there is a long way to go to treat cancers. Resistance to anti-cancer drugs results from various factors, including genetic as well as epigenetic differences in tumors. Determining the molecular and cellular mechanisms responsible for the acquisition of drug resistance may be a helpful approach for the development of new therapeutic strategies to overcome treatment failure. Several studies have shown that the acquisition of drug resistance is tightly regulated by post-transcriptional regulators such as RNA binding proteins (RBPs) and microRNAs (miRNAs), which change the stability and translation of mRNAs encoding factors involved in cell survival, proliferation, epithelial-mesenchymal transition, and drug metabolism. Here, we review our current understanding of ribonucleoprotein complexes, including RBPs and miRNAs, which play critical roles in the acquisition of drug resistance and have potential clinical implications for cancer.

A Long Non-Coding RNA snaR Contributes to 5-Fluorouracil Resistance in Human Colon Cancer Cells

“…Although chemotherapy has been widely used for cancer treatment, acquisition of drug resistance is considered a substantial obstacle in effective chemotherapy (Kang et al, 2013). Altered expression or mutation of transporter proteins that increase drug efflux from cancer cells, reduce uptake of drugs, increase repair of DNA damage, decrease sensitivity resulting from induction of apoptosis, and accelerate drug metabolism are responsible for the development of drug resistance (Fojo, 2007;Glasspool et al, 2006;Roberti et al, 2006;Tan et al, 2010).…”

Promoter demethylation of nuclear factor-erythroid 2-related factor 2 gene in drug-resistant colon cancer cells

“…Chemotherapy is widely used for the treatment of cancer; however, acquired drug resistance is considered to be a substantial obstacle for effective chemotherapy (1). Drug resistance is a phenomenon that occurs due to a combination of factors and may involve individual differences in patients as well as genetic and epigenetic variations in tumors (2,3).…”

Epigenetics of Brain Disorders: The Paradigm of Alzheimer ’s Disease

“…Individual differences in drug response are associated with genetic and epigenetic variability and disease determinants [111,112]. The genes involved in the pharmacogenomic response to drugs fall into five major categories: (i) genes associated with disease pathogenesis; (ii) genes associated with the mechanism of action of drugs (enzymes, receptors, transmitters, messengers); (iii) genes associated with drug metabolism: (a) phase I reaction enzymes: alcohol dehydrogenases, aldehyde dehydrogenases, aldo-keto reductases, amine oxidases, carbonyl reductases, cytidine deaminase, cytochrome P450 enzyme family, cytochrome b5 reductase, dihydroprimidine dehydrogenase, esterases, epoxidases, flavin-containing monooxygenases, glutathione reductase/peroxidases, short-chain dehydrogenases/reductases, superoxide dismutases, and xanthine dehydrogenase; and (b): phase II reaction enzymes: amino acid transferases, dehydrogenases, esterases, glucuronosyl transferases, glutathione transferases, methyl transferases, N-acetyl transferases, thioltransferase, and sulfotransferases; (iv) genes associated with drug transporters: ABC genes, especially ABCB1 (ATPbinding cassette, subfamily B, member 1; P-glycoprotein-1, P-gp1; Multidrug Resistance 1, MDR1), ABCC1, ABCG2 (White1), genes of the solute carrier superfamily (SLC) and solute carrier organic (SLCO) transporter family, responsible for the transport of multiple endogenous and exogenous compounds, including folate (SLC19A1), urea (SLC14A1, SLC14A2), monoamines (SLC29A4, SLC22A3), aminoacids (SLC1A5, SLC3A1, SLC7A3, SLC7A9, SLC38A1, SLC38A4, SLC38A5, SLC38A7, SLC43A2, SLC45A1), nucleotides (SLC29A2, SLC29A3), fatty acids (SLC27A1-6), neurotransmitters (SLC6A2 (noradrenaline transporter), SLC6A3 (dopamine transporter), SLC6A4 (serotonin transporter, SERT), SLC6A5, SLC6A6, SLC6A9, SLC6A11, SLC6A12, SLC6A14, SLC6A15, SLC6A16, SLC6A17, SLC6A18, SLC6A19), glutamate (SLC1A6, SLC1A7), and others); and (v) pleiotropic genes involved in multifaceted cascades and metabolic reactions [3,[113][114][115][116][117] (Tables 3 and 4). …”

“…Epigenetic modifications are also associated with drug resistance [116][117][118][119]. The acquisition of drug resistance is tightly regulated by post-transcriptional regulators such as RNA-binding proteins (RBPs) and miRNAs, which change the stability and translation of mRNA encoding factors involved in cell survival, proliferation, epithelialmesenchymal transition, and drug metabolism [116,117].…”

“…Epigenetic changes affect cytochrome P450 enzyme expression, major transporter function, and nuclear receptor interactions [114][115][116][117]. Although this is a still poorly explored field, epigenetic regulation of genes encoding drug-metabolizing enzymes (CYP1A1, 1A2, 1B1, 1A6, 2A13, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 2J2, 2F1, 2R1, 2S1, 2W1, 3A4, 3A5, 3A7, 3A43, UGT1, GSTP1), drug transporters (ABCB1/MDR1/P-gp, ABCC1/MRP1, ABCC11/MRP8, ABCG2/BCRP, SLC19A1, SLC22A8), and nuclear receptors (RARB2, ESR1, NR1I2, HNF41) has been documented in pioneering studies of pharmacoepigenetics [111][112][113][114][115][116][117][118] (Table 5).…”