Natural populations exhibit a great deal of interindividual genetic variation in the response to toxins, exemplified by the variable clinical efficacy of pharmaceutical drugs in humans, and the evolution of pesticide resistant insects. Such variation can result from several phenomena, including variable metabolic detoxification of the xenobiotic, and differential sensitivity of the molecular target of the toxin. Our goal is to genetically dissect variation in the response to xenobiotics, and characterize naturally-segregating polymorphisms that modulate toxicity. Here, we use the Drosophila Synthetic Population Resource (DSPR), a multiparent advanced intercross panel of recombinant inbred lines, to identify QTL (Quantitative Trait Loci) underlying xenobiotic resistance, and employ caffeine as a model toxic compound. Phenotyping over 1,700 genotypes led to the identification of ten QTL, each explaining 4.5–14.4% of the broad-sense heritability for caffeine resistance. Four QTL harbor members of the cytochrome P450 family of detoxification enzymes, which represent strong a priori candidate genes. The case is especially strong for Cyp12d1, with multiple lines of evidence indicating the gene causally impacts caffeine resistance. Cyp12d1 is implicated by QTL mapped in both panels of DSPR RILs, is significantly upregulated in the presence of caffeine, and RNAi knockdown robustly decreases caffeine tolerance. Furthermore, copy number variation at Cyp12d1 is strongly associated with phenotype in the DSPR, with a trend in the same direction observed in the DGRP (Drosophila Genetic Reference Panel). No additional plausible causative polymorphisms were observed in a full genomewide association study in the DGRP, or in analyses restricted to QTL regions mapped in the DSPR. Just as in human populations, replicating modest-effect, naturally-segregating causative variants in an association study framework in flies will likely require very large sample sizes.
Chemo/radio-therapy resistance to the deadly pancreatic cancer is mainly due to the failure to kill pancreatic cancer stem cells (CSCs). Signal transducer and activator of transcription 3 (STAT3) is activated in pancreatic CSCs and, therefore, may be a valid target for overcoming therapeutic resistance. Here we investigated the potential of STAT3 inhibition in sensitizing pancreatic cancer to chemo/radio-therapy. We found that the levels of nuclear pSTAT3 in pancreatic cancer correlated with advanced tumor grade and poor patient outcome. Liposomal delivery of a STAT3 inhibitor FLLL32 (Lip-FLLL32) inhibited STAT3 phosphorylation and STAT3 target genes in pancreatic cancer cells and tumors. Consequently, Lip-FLLL32 suppressed pancreatic cancer cell growth, and exhibited synergetic effects with gemcitabine and radiation treatment in vitro and in vivo. Furthermore, Lip-FLLL32 reduced ALDH1-positive CSC population and modulated several potential stem cell markers. These results demonstrate that Lip-FLLL32 suppresses pancreatic tumor growth and sensitizes pancreatic cancer cells to radiotherapy through inhibition of CSCs in a STAT3-dependent manner. By targeting pancreatic CSCs, Lip-FLLL32 provides a novel strategy for pancreatic cancer therapy via overcoming radioresistance.
2 21 ABSTRACT 22 Illicit use of psychostimulants, such as cocaine and methamphetamine, constitutes a significant 23 public health problem. Whereas neural mechanisms that mediate the effects of these drugs are 24 well-characterized, genetic factors that account for individual variation in susceptibility to 25 substance abuse and addiction remain largely unknown. Drosophila melanogaster can serve as 26 a translational model for studies on substance abuse, since flies have a dopamine transporter 27 that can bind cocaine and methamphetamine, and exposure to these compounds elicits effects 28 similar to those observed in people, suggesting conserved evolutionary mechanisms underlying 29 drug responses. Here, we used the D. melanogaster Genetic Reference Panel to investigate the 30 genetic basis for variation in psychostimulant drug consumption, to determine whether similar or 31 distinct genetic networks underlie variation in consumption of cocaine and methamphetamine, 32 and to assess the extent of sexual dimorphism and effect of genetic context on variation in 33 voluntary drug consumption. Quantification of natural genetic variation in voluntary 34 consumption, preference, and change in consumption and preference over time for cocaine and 35 methamphetamine uncovered significant genetic variation for all traits, including sex-, exposure-36 and drug-specific genetic variation. Genome wide association analyses identified both shared 37 and drug-specific candidate genes, which could be integrated in genetic interaction networks. 38 We assessed the effects of ubiquitous RNA interference (RNAi) on consumption behaviors for 39 34 candidate genes: all affected at least one behavior. Finally, we utilized RNAi knockdown in 40 the nervous system to implicate dopaminergic neurons and the mushroom bodies as part of the 41 neural circuitry underlying experience-dependent development of drug preference. 42 3 43 AUTHOR SUMMARY 44 Illicit use of cocaine and methamphetamine is a major public health problem. Whereas the 45 neurological effects of these drugs are well characterized, it remains challenging to determine 46 genetic risk factors for substance abuse in human populations. The fruit fly, Drosophila 58 projection plays a role in drug addiction. We asked whether in Drosophila the mushroom bodies 59 could play an analogous role, as they are integrative brain centers associated with experience-60 dependent learning. Indeed, our results suggest that variation in consumption and development 61 of preference for both cocaine and methamphetamine is mediated, at least in part, through a 62 neural network that comprises dopaminergic projections to the mushroom bodies. 63 4 65 130 expression in neurons, glia, the mushroom bodies and dopaminergic neurons in a subset of 131 genes and showed that innate preference and the development of preference for 132 psychostimulant drugs involves dopaminergic neurons and the mushroom bodies, neural 133 elements associated with experience-dependent modulation of behavior. 134 135 RESULTS 136 Quantit...
Illicit use of psychostimulants, such as cocaine and methamphetamine, constitutes a significant public health problem. Whereas neural mechanisms that mediate the effects of these drugs are well-characterized, genetic factors that account for individual variation in susceptibility to substance abuse and addiction remain largely unknown. Drosophila melanogaster can serve as a translational model for studies on substance abuse, since flies have a dopamine transporter that can bind cocaine and methamphetamine, and exposure to these compounds elicits effects similar to those observed in people, suggesting conserved evolutionary mechanisms underlying drug responses. Here, we used the D . melanogaster Genetic Reference Panel to investigate the genetic basis for variation in psychostimulant drug consumption, to determine whether similar or distinct genetic networks underlie variation in consumption of cocaine and methamphetamine, and to assess the extent of sexual dimorphism and effect of genetic context on variation in voluntary drug consumption. Quantification of natural genetic variation in voluntary consumption, preference, and change in consumption and preference over time for cocaine and methamphetamine uncovered significant genetic variation for all traits, including sex-, exposure- and drug-specific genetic variation. Genome wide association analyses identified both shared and drug-specific candidate genes, which could be integrated in genetic interaction networks. We assessed the effects of ubiquitous RNA interference (RNAi) on consumption behaviors for 34 candidate genes: all affected at least one behavior. Finally, we utilized RNAi knockdown in the nervous system to implicate dopaminergic neurons and the mushroom bodies as part of the neural circuitry underlying experience-dependent development of drug preference.
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