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7-Ketocholesterol overcomes drug resistance in Chronic Myeloid Leukemia cell lines beyond MDR1 mechanism_part1

ABSTRACT: Chronic myeloid leukemia (CML) is a myeloproliferative disease with a characteristic BCR-ABL tyrosine kinase (TK) fusion protein. Despite the clinical efficacy accomplished by TKIs therapies disease progression may affect patient response rate to these inhibitors due to a multitude of factors that could lead to development of a mechanism known as multidrug resistance (MDR). 7-ketocholesterol (7KC) has been extensively reported to cause cell death in a variety of cancer models. In this study, we showed the in vitro efficacy of 7KC against MDR leukemia cell line, Lucena. 7KC treatment induced reduction in cell viability, together with apoptosis-mediated cell death. Moreover, downregulation of MDR protein caused intracellular drug accumulation and 7KC co-incubation with either Daunorubicin or Vincristine reduced cell viability compared to the use of each drug alone. Additionally, quantitative label-free mass spectrometry-based protein quantification showed alteration of different molecular pathways involved in cell cycle arrest, induction of apoptosis and misfolded protein response. Conclusively, this study highlights the effect of 7KC as a sensitizing agent of multidrug resistance CML and elucidate its molecular mechanisms.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Chronic Myeloid Leukemia

SUBMITTER: Giuseppe Palmisano

LAB HEAD: Giuseppe Palmisano

PROVIDER: PXD003816 | Pride | 2022-03-07

REPOSITORIES: Pride

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7-Ketocholesterol overcomes drug resistance in Chronic Myeloid Leukemia cell lines beyond MDR1 mechanism_part2

Project description:Chronic myeloid leukemia (CML) is a myeloproliferative disease with a characteristic BCR-ABL tyrosine kinase (TK) fusion protein. Despite the clinical efficacy accomplished by TKIs therapies disease progression may affect patient response rate to these inhibitors due to a multitude of factors that could lead to development of a mechanism known as multidrug resistance (MDR). 7-ketocholesterol (7KC) has been extensively reported to cause cell death in a variety of cancer models. In this study, we showed the in vitro efficacy of 7KC against MDR leukemia cell line, Lucena. 7KC treatment induced reduction in cell viability, together with apoptosis-mediated cell death. Moreover, downregulation of MDR protein caused intracellular drug accumulation and 7KC co-incubation with either Daunorubicin or Vincristine reduced cell viability compared to the use of each drug alone. Additionally, quantitative label-free mass spectrometry-based protein quantification showed alteration of different molecular pathways involved in cell cycle arrest, induction of apoptosis and misfolded protein response. Conclusively, this study highlights the effect of 7KC as a sensitizing agent of multidrug resistance CML and elucidate its molecular mechanisms.

2022-03-07 | PXD003819 | Pride

7-Ketocholesterol overcomes drug resistance in Chronic Myeloid Leukemia cell lines beyond MDR1 mechanism_part3

2022-03-07 | PXD003820 | Pride

Changes in the expression of miR-381 and miR-495 are inversely associated with the expression of the MDR1 gene and development of multi-drug resistance

Project description:Multidrug resistance (MDR) frequently develops in cancer patients exposed to chemotherapeutic agents and is usually brought about by over-expression of P-glycoprotein (P-gp) which acts as a drug efflux pump. MiRNAome profiling using next-generation sequencing identified differentially expressed microRNAs (miRs) between parental K562 cells and MDR K562 cells (K562/ADM) induced by chronic adriamycin treatment. MiRNAome profiling in untreated K562 cells and K562 cells exposed to long-term adriamycin treatment

2013-10-29 | E-GEOD-51774 | biostudies-arrayexpress

Global microRNA profiling of mouse hemopoietic stem cells (LSKs), promyelocytes, myelocytes and granulocytes.

Project description:This study sought to determine the dynamic changes of miRNA expression during mouse granulopoiesis. We not only performed analyses of miRNA expression levels in whole cells but also analyzed purified nuclear and cytoplasmic cell fractions to profile miRNA subcellular localization. qRT-PCR analysis of miRNAs was performed on whole cell, nuclear and cytoplasmic RNAs extracted from mouse hemopoietic stem cells (LSKs), promyelocytes, myelocytes and granulocytes. 100 ng of RNA was reversed transcribed using the Taqman miRNA Reverse Transcription Kit and Megaplex RT Primers rodent pool A and B (Life Technologies). Complementary DNA (cDNA) was amplified using a TaqMan rodent microRNA A and B Array v2.0 (Life Technologies) with TaqMan Universal PCR Master Mix on an ABI 7900HT Sequence Detection System.

2014-05-14 | E-GEOD-57623 | biostudies-arrayexpress

Comprehensive proteome profiling of nuclear and cytoplasmic fractions of rat Sertoli cells.

2017-01-18 | PXD003050 | Pride

SWATH-MS analysis of nuclear and cytoplasmic fractions of rat Sertoli cells

Project description:The Sertoli cells (Sc) of 5 days (infant) and 12 days (pubertal) old rat were isolated and cultured in triplicates. Nuclear and cytoplasmic fractionation was done for both the cases. All the four protein fractions (nuclear and cytoplasm of infant and pubertal Sc) were anaysed using Lc-MS/MS. SWATH analysis was done for all the four samples in biological and technical replicates. The objective was to quantity the proteins of all the samples with respect to each other at whole proteome level.

2017-01-18 | PXD003056 | Pride

HSCB KO vs NC K562 cells TMT LC/MS

Project description:We utilized tandem mass tag (TMT)-based mass spectrometry to characterize nuclear proteomic changes between HSCB KO and NC K562 cells.

2024-05-16 | PXD041272 | Pride

small RNA profiling in human cell line following Dicer silencing

Project description:microRNAs (miRNAs) are a large class of small non-coding RNAs which post-transcriptionally regulate the expression of a large fraction of all animal genes and are important in a wide range of biological processes. Recent advances in high-throughput sequencing allow miRNA detection at unprecedented sensitivity, but the computational task of accurately identifying the miRNAs in the background of sequenced RNAs remains challenging. For this purpose we have designed miRDeep2, a substantially improved algorithm which identifies canonical and non-canonical miRNAs such as those derived from transposable elements and informs on high-confidence candidates that are detected in multiple independent samples. Analyzing data from seven animal species representing the major animal clades, miRDeep2 identified miRNAs with an accuracy of 98.6-99.9% and reported hundreds of novel miRNAs. To test the accuracy of miRDeep2, we knocked down the miRNA biogenesis pathway in a human cell line and sequenced small RNAs before and after. The vast majority of the >100 novel miRNAs expressed in this cell line were indeed specifically down-regulated, validating most miRDeep2 predictions. Last, a new miRNA expression profiling routine, low time and memory usage and user-friendly interactive graphic output can make miRDeep2 useful to a wide range of researchers." high-throughput sequencing was used to profile small RNA expression in a human MCF-7 cell line before and after Dicer knock-down

2011-09-12 | E-GEOD-31069 | biostudies-arrayexpress

Genomic profiling of imatinib resistant and sensitive K562 cells to obtain insights into imatinib resistance

Project description:Chronic myeloid leukemia (CML) epitomizes successful targeted therapy, with 86% of patients in the chronic phase treated with tyrosine kinase inhibitors (TKIs) attaining remission. However, resistance to TKIs occurs during treatment, and patients with resistance to TKIs progress to the acute phase called Blast Crisis (BC), wherein the survival is restricted to 7-11 months. About 80 % of patients in BC are unresponsive to TKIs. This issue can be addressed by identifying a molecular signature which can predict resistance in CML-CP prior to treatment as well as by delineating the molecular mechanism underlying resistance. Herein, we report genomic analysis of CML patients and imatinib-resistant K562 cell line to achieve the same. WGS was performed on imatinib-sensitive and -resistant K562 cells. Library preparation was done by 30x WGS KAPA PCR-Free v2.1 kit, and Illumina HiSeq X sequencer was used for 2 x 150 bp paired-end sequencing. Our study identified accumulation of aberrations on chromosomes 1, 3, 7, 16 and 22 as predictive of occurrence of resistance. Further, recurrent amplification in chromosomal region 8q11.2-12.1 was detected in highly resistant K562 cells as well as CML patients. The genes present in this region were analyzed to understand molecular mechanism of imatinib resistance.

2024-01-01 | E-MTAB-11896 | biostudies-arrayexpress

miRNA profile of THP-1 macrophage infected with different MTB strains

Project description:We examined the microRNA profiles of THP-1 macrophages upon the MTB infection of (1) Beijing/W and non-Beijing/W clinical strains, and (2) susceptible and multidrug-resistant (MDR-) MTB strains. THP-1 cells were induced differentiation into a macrophage phenotype. Then cells were infected with three MDR (INHR, RIFR) Beijing/W, three sensitive (INHS, RIFS) Beijing/W, three MDR(INHR, RIFR) non-Beijing/W, and three sensitive (INHS, RIFS) non-Beijing/W strains. Total RNA were extracted and transfered into cDNA for miRNA profile analysis. Non-infected cells were used as control.

2015-07-01 | E-GEOD-65811 | biostudies-arrayexpress

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