Molecular pathways: regulation and therapeutic implications of multidrug resistance

Abstract

Multidrug transporters constitute major mechanisms of MDR in human cancers. The ABCB1 (MDR1) gene encodes a well-characterized transmembrane transporter, termed P-glycoprotein (P-gp), which is expressed in many normal human tissues and cancers. P-gp plays a major role in the distribution and excretion of drugs and is involved in intrinsic and acquired drug resistance of cancers. The regulation of ABCB1 expression is complex and has not been well studied in a clinical setting. In this review, we elucidate molecular signaling and epigenetic interactions that govern ABCB1 expression and the development of MDR in cancer. We focus on acquired expression of ABCB1 that is associated with genomic instability of cancer cells, including mutational events that alter chromatin structures, gene rearrangements, and mutations in tumor suppressor proteins (e.g., mutant p53), which guard the integrity of genome. In addition, epigenetic modifications of the ABCB1 proximal and far upstream promoters by either demethylation of DNA or acetylation of histone H3 play a pivotal role in inducing ABCB1 expression. We describe a molecular network that coordinates genetic and epigenetic events leading to the activation of ABCB1. These mechanistic insights provide additional translational targets and potential strategies to deal with clinical MDR.

©2012 AACR.

Figures

Figure 1. Cooperation and coordination of signaling networks of multidrug resistance

Drug-resistance activating signals produce pleiotropic effects that lead to transactivation and coordination of various drug resistance programs. The drug-resistance activating system includes the p53 networks, anti-apoptotic pathways, JAK/STAT pathways, Ras-based MAPK pathways, classical MDR genes such as ABCB1, ABCG2, and ABCC1, and other alternative forms of drug resistance mechanisms. Transcriptional activator complexes for the ABCB1 gene are likely shared by a large set of transcriptional factors that are involved in conferring drug resistance and cell survival. Transcription repressors that prevent the assembly of activator complexes are dissociated from promoters of the target genes prior to ABCB1 activation. These derepression mechanisms are modulated by the genomic instability of cancers, epigenetic modifications of histones, and tissue-specific factors. The yellow arrows indicate activation or positive regulation, whereas the red line indicators denote suppression or negative regulation. Question marks indicate hypothetical or undefined factors or pathways. Abbreviations: ABCB1 P1, the ABCB1 proximal promoter; Ac, acetylated histone; AKT, v-akt murine thymoma viral oncogene homolog; AP-1, the activator protein 1 (a transcription factor); c-Jun, a transcriptional factor encoded by the Jun proto-oncogene; ERK, extracellular signal-regulated kinase; gp130, glycoprotein 130; GPCR, G protein-coupled receptor; HAT, histone acetyltransferase; HDAC, histone deacetylases; Her2, human epidermal growth factor receptor 2; IGF-1, insulin-like growth factor 1; IL-6, interleukin-6; IL-6R, Interleukin-6 receptor; JAK, Janus kinase; JNK1, c-Jun N-terminal kinase; MDM2, Mdm2 p53 binding protein homolog (mouse); MDR, multidrug resistance; MeCP2, methyl CpG binding protein 2; MEK, mitogen-activated protein kinase kinase; mTOR, the mammalian target of rapamycin; p53, the tumor suppressor protein p53; pCAF, p300/CBP-associated factor; PM, plasma membrane; Pol II, RNA polymerase II; Raf, a proto-oncogene serine/threonine-protein kinase; Ras, a protein subfamily of small GTPases; STAT, signal transducer and activator of transcription; SWI/SNF, a nucleosome remodeling complex.

Figure 1. Cooperation and coordination of signaling networks of multidrug resistance

Drug-resistance activating signals produce pleiotropic effects that lead to transactivation and coordination of various drug resistance programs. The drug-resistance activating system includes the p53 networks, anti-apoptotic pathways, JAK/STAT pathways, Ras-based MAPK pathways, classical MDR genes such as ABCB1, ABCG2, and ABCC1, and other alternative forms of drug resistance mechanisms. Transcriptional activator complexes for the ABCB1 gene are likely shared by a large set of transcriptional factors that are involved in conferring drug resistance and cell survival. Transcription repressors that prevent the assembly of activator complexes are dissociated from promoters of the target genes prior to ABCB1 activation. These derepression mechanisms are modulated by the genomic instability of cancers, epigenetic modifications of histones, and tissue-specific factors. The yellow arrows indicate activation or positive regulation, whereas the red line indicators denote suppression or negative regulation. Question marks indicate hypothetical or undefined factors or pathways. Abbreviations: ABCB1 P1, the ABCB1 proximal promoter; Ac, acetylated histone; AKT, v-akt murine thymoma viral oncogene homolog; AP-1, the activator protein 1 (a transcription factor); c-Jun, a transcriptional factor encoded by the Jun proto-oncogene; ERK, extracellular signal-regulated kinase; gp130, glycoprotein 130; GPCR, G protein-coupled receptor; HAT, histone acetyltransferase; HDAC, histone deacetylases; Her2, human epidermal growth factor receptor 2; IGF-1, insulin-like growth factor 1; IL-6, interleukin-6; IL-6R, Interleukin-6 receptor; JAK, Janus kinase; JNK1, c-Jun N-terminal kinase; MDM2, Mdm2 p53 binding protein homolog (mouse); MDR, multidrug resistance; MeCP2, methyl CpG binding protein 2; MEK, mitogen-activated protein kinase kinase; mTOR, the mammalian target of rapamycin; p53, the tumor suppressor protein p53; pCAF, p300/CBP-associated factor; PM, plasma membrane; Pol II, RNA polymerase II; Raf, a proto-oncogene serine/threonine-protein kinase; Ras, a protein subfamily of small GTPases; STAT, signal transducer and activator of transcription; SWI/SNF, a nucleosome remodeling complex.