Differential Processing of let-7a Precursors Influences RRM2 Expression and Chemosensitivity in Pancreatic Cancer: Role of LIN-28 and SET Oncoprotein

Bhutia, Yangzom D.; Hung, Sau Wai; Krentz, Madeline; Patel, Dimal; Lovin, Dylan; Manoharan, Radhika; Thomson, J. Michael; Govindarajan, Rajgopal

doi:10.1371/journal.pone.0053436

Cited by 70 publications

(56 citation statements)

References 46 publications

(69 reference statements)

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“…miR-211 can reduce the expression of RRM2, the important cellular target of gemcitabine, and increase the sensitivity of pancreatic cancer cells to gemcitabine 170 . miRNA let-7 was also found to negatively regulate RRM2 expression and sensitize PDAC cells to gemcitabine 171 .…”

Section: Aberrant Expression Of Mirnas and Cancer Drug Resistancementioning

confidence: 95%

Regulation of multidrug resistance by microRNAs in anti-cancer therapy

An¹,

Sarmiento

Tan

et al. 2017

Acta Pharmaceutica Sinica B

162

132

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Multidrug resistance (MDR) remains a major clinical obstacle to successful cancer treatment. Although diverse mechanisms of MDR have been well elucidated, such as dysregulation of drugs transporters, defects of apoptosis and autophagy machinery, alterations of drug metabolism and drug targets, disrupti on of redox homeostasis, the exact mechanisms of MDR in a specific cancer patient and the cross-talk among these different mechanisms and how they are regulated are poorly understood. MicroRNAs (miRNAs) are a new class of small noncoding RNAs that could control the global activity of the cell by post-transcriptionally regulating a large variety of target genes and proteins expression. Accumulating evidence shows that miRNAs play a key regulatory role in MDR through modulating various drug resistant mechanisms mentioned above, thereby holding much promise for developing novel and more effective individualized therapies for cancer treatment. This review summarizes the various MDR mechanisms and mainly focuses on the role of miRNAs in regulating MDR in cancer treatment.

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Section: Aberrant Expression Of Mirnas and Cancer Drug Resistancementioning

confidence: 95%

Regulation of multidrug resistance by microRNAs in anti-cancer therapy

An¹,

Sarmiento

Tan

et al. 2017

Acta Pharmaceutica Sinica B

162

132

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“…Both HPDE and L3.6pl cell lines were handled as other cell lines and were genotyped by DNA fingerprinting (PowerPlex 16; Promega, Madison, WI) as per the manufacturer’s instructions. The growth conditions of cell lines were performed as described previously (26). Panc 10.05 was grown in RPMI-1640 Medium with 15% FBS and 10 U/ml human recombinant insulin while CFPAC-1 was grown in Iscove’s Modified Dulbecco’s Medium with 10% FBS.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of S-Adenosylmethionine-Dependent Methyltransferase Attenuates TGFβ1-Induced EMT and Metastasis in Pancreatic Cancer: Putative Roles of miR-663a and miR-4787-5p

Mody

Hung

Alsaggar

et al. 2016

Molecular Cancer Research

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Identification of epigenetic reversal agents for use in combination chemotherapies to treat human pancreatic ductal adenocarcinomas (PDAC) remains an unmet clinical need. Pharmacological inhibitors of Enhancer of Zeste Homolog 2 (EZH2) are emerging as potential histone methylation reversal agents for the treatment of various solid tumors and leukemia; however, the surprisingly small set of mRNA targets identified with EZH2 knockdown suggests novel mechanisms contribute to their anti-tumorigenic effects. Here, 3-deazaneplanocin-A (DZNep), an inhibitor of S-adenosyl-L-homocysteine hydrolase and EZH2 histone lysine-N-methyltransferase, significantly reprograms noncoding miRNA (miR) expression and dampens TGFβ1-induced epithelial-to-mesenchymal (EMT) signals in pancreatic cancer. In particular, miR-663a and miR-4787-5p were identified as PDAC-downregulated miRs that were reactivated by DZNep to directly target TGFβ1 for RNA interference. Lentiviral overexpression of miR-663a and miR-4787-5p reduced TGFβ1 synthesis and secretion in PDAC cells and partially phenocopied DZNep’s EMT-resisting effects, whereas locked nucleic acid (LNA) antagomiRs counteracted them. DZNep, miR-663a, and miR-4787-5p reduced tumor burden in vivo and metastases in an orthotopic mouse pancreatic tumor model. Taken together, these findings suggest the epigenetic reprogramming of miRs by synthetic histone methylation reversal agents as a viable approach to attenuate TGFβ1-induced EMT features in human PDAC and uncover putative miR targets involved in the process.

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“…The diphosphate form of gemcitabine is a potent inhibitor of the ribonucleotide reductase activity (needed for DNA synthesis) coded for by these two genes (Whirl-Carrillo et al 2012). Bhutia et al (2013) showed that overexpression of RRM2 drives the chemoresistance of pancreatic cancer to gemcitabine. Additionally, it has been shown that prolonged exposure of cancer cells to triapine, an inhibitor of ribonucleotide reductase, enhances gemcitabine activity in vitro (Mortazavi et al 2013).…”

Section: Chemotoxicity Qtlmentioning

confidence: 99%

Using Drosophila melanogaster To Identify Chemotherapy Toxicity Genes

King

Kislukhin

Walters³

et al. 2014

Genetics

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The severity of the toxic side effects of chemotherapy shows a great deal of interindividual variability, and much of this variation is likely genetically based. Simple DNA tests predictive of toxic side effects could revolutionize the way chemotherapy is carried out. Due to the challenges in identifying polymorphisms that affect toxicity in humans, we use Drosophila fecundity following oral exposure to carboplatin, gemcitabine and mitomycin C as a model system to identify naturally occurring DNA variants predictive of toxicity. We use the Drosophila Synthetic Population Resource (DSPR), a panel of recombinant inbred lines derived from a multiparent advanced intercross, to map quantitative trait loci affecting chemotoxicity. We identify two QTL each for carboplatin and gemcitabine toxicity and none for mitomycin. One QTL is associated with fly orthologs of a priori human carboplatin candidate genes ABCC2 and MSH2, and a second QTL is associated with fly orthologs of human gemcitabine candidate genes RRM2 and RRM2B. The third, a carboplatin QTL, is associated with a posteriori human orthologs from solute carrier family 7A, INPP4A&B, and NALCN. The fourth, a gemcitabine QTL that also affects methotrexate toxicity, is associated with human ortholog GPx4. Mapped QTL each explain a significant fraction of variation in toxicity, yet individual SNPs and transposable elements in the candidate gene regions fail to singly explain QTL peaks. Furthermore, estimates of founder haplotype effects are consistent with genes harboring several segregating functional alleles. We find little evidence for nonsynonymous SNPs explaining mapped QTL; thus it seems likely that standing variation in toxicity is due to regulatory alleles. CHEMOTHERAPEUTIC agents are among the most toxic medications administered to humans (Alley et al. 2002). The toxicity caused by these medications may become severe enough that patients are forced to adjust dosing or switch to a different chemotherapeutic medication, while the disease progresses. Although diet, medical history, age, and other environmental factors of the patient may explain a portion of the toxicity (Gajewski et al. 1989;Meirow and Nugent 2001; Rothenberg et al. 2003;Watters and McLeod 2003;Lee et al. 2005), we have shown that there is a significant genetic component governing the toxic effect of several drugs in Drosophila melanogaster (Kislukhin et al. 2012). Here we use the D. melanogaster model system to dissect the genetic basis of toxicity for three front-line chemotherapeutics: carboplatin, gemcitabine hydrochloride (gemcitabine), and mitomycin C.Carboplatin is a platinum-containing compound used primarily to treat ovarian cancer. It is also sometimes used to treat lung, breast, bladder, and endometrial cancer; head and neck cancer; cancer of the cervix and testicles; certain types of brain cancer; Wilms' tumor; neuroblastoma; and retinoblastoma (Wheate et al. 2010). Gemcitabine is an antimetabolite used primarily in combination with other chemotherapy drugs to treat ovarian...

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Differential Processing of let-7a Precursors Influences RRM2 Expression and Chemosensitivity in Pancreatic Cancer: Role of LIN-28 and SET Oncoprotein

Cited by 70 publications

References 46 publications

Regulation of multidrug resistance by microRNAs in anti-cancer therapy

Regulation of multidrug resistance by microRNAs in anti-cancer therapy

Inhibition of S-Adenosylmethionine-Dependent Methyltransferase Attenuates TGFβ1-Induced EMT and Metastasis in Pancreatic Cancer: Putative Roles of miR-663a and miR-4787-5p

Using Drosophila melanogaster To Identify Chemotherapy Toxicity Genes

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