MicroRNA expression profiles for the NCI-60 cancer cell panel

Blower, Paul E.; Verducci, Joseph S.; Lin, Shili; Zhou, Jin; Chung, Ji Hyun; Dai, Zunyan; Liu, Chang Gong; Reinhold, William C.; Lorenzi, Philip L.; Kaldjian, Eric P.; Croce, Carlo M.; Weinstein, John N.; Sadée, Wolfgang

doi:10.1158/1535-7163.mct-07-0009

Cited by 225 publications

(190 citation statements)

References 45 publications

(43 reference statements)

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“…As such, they have been used extensively as experimental models of cancer. In general, the expression patterns of the different cell-lines seen in the National Cancer Institute's NCI60 microarray are relatively consistent with the primary tissue type when the clustering is based on mRNA expression patterns 437,438 .…”

Section: The Expression Profile Of Bfl-1 In the Nci60 Microarraymentioning

confidence: 88%

“…These celllines have been examined by microarray analysis for gene expression patterns to give an NCI60 array 437 , which has been used to examine mRNA and protein expression, chromosomal aberrations, DNA copy number and mutational status, with all this data made available as a public resource (http://biogps.gnf.org/). In fact a selection of ninety three cell-lines derived from twenty two different cancer types are now present in the array 438 .…”

Section: The Expression Profile Of Bfl-1 In the Nci60 Microarraymentioning

confidence: 99%

“…Furthermore, the National Cancer Institute's database of cell-lines derived from a selection of cancers (the NCI60) suggests that the expression patterns of mRNA remains largely similar between the cell-lines and the original tissues from which they are derived 437,438 . The NCI60 microarray measured the level of Bfl-1 mRNA, but within the panel of melanoma cell-lines I was able to explore the expression levels of both the protein and mRNA, which were both highly expressed in five out of our six melanoma cell-lines.…”

Section: : Concluding Remarksmentioning

confidence: 99%

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Role of the pro-survival molecule Bfl-1 in melanoma

Hind

Carter

Harris

et al. 2015

The International Journal of Biochemistry & Cell Biology

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Melanoma, the cancer derived from the melanocytes of the skin, is becoming an ever more common cancer in the ageing population of the developed world and displays an intrinsic resistance to current therapies. This chemo resistance makes metastatic melanoma an extremely difficult cancer to treat leading to a 5 year survival rate of just 20%. As such, it is important to unearth new potential drug targets to increase the prospects for melanoma patients.Bfl-1 is a pro-survival protein of the Bcl-2 family of apoptosis regulating proteins. It has been found to be over-expressed in a small subset of chemo resistant tumours, including melanoma. Accordingly, I characterised the molecule in melanoma cells and determined its role in protecting these cells from chemotherapy-induced apoptosis. I elucidated the expression profile and half-lives of the protein and mRNA across a panel of melanoma cell-lines and healthy melanocytes. I also confirmed, using pathway specific inhibitors, that Bfl-1 was transcriptionally regulated by the NFB pathway and concluded through pulsechase experiments that Bfl-1 protein was degraded, at least in part, by the proteasome. Subcellular fractionation and indirect immunofluorescence techniques elucidated that Bfl-1 was located mostly at the mitochondria in both resting and apoptotic cells, with a diffuse level present throughout the cytoplasm. As well as characterising the protein in both melanoma cells and healthy primary melanocytes, I determined its role in the resistance of these cells to apoptosis. Over-expressed Bfl-1 was found to protect melanoma cells from apoptosis caused by a range of chemotherapeutic agents in A375 melanoma cells, which naturally expressed very low levels of Bfl-1. Further, knock down of Bfl-1 using siRNA technology in melanoma cells revealed the dependence of these cells on Bfl-1 for their resistance to certain chemotherapeutic agents currently used in melanoma treatment, including the MEK inhibitor PD901. All together, this research contributes to our understanding of Bfl-1 and highlights it as a potentially important therapeutic target in metastatic melanoma.

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Section: The Expression Profile Of Bfl-1 In the Nci60 Microarraymentioning

confidence: 88%

Section: The Expression Profile Of Bfl-1 In the Nci60 Microarraymentioning

confidence: 99%

Section: : Concluding Remarksmentioning

confidence: 99%

See 1 more Smart Citation

Role of the pro-survival molecule Bfl-1 in melanoma

Hind

Carter

Harris

et al. 2015

The International Journal of Biochemistry & Cell Biology

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“…To explore the anticancer mechanisms of oridonin, we generated oligonucleotide DNA arrays for detection of miRNA expression because accumulating evidence suggested that miRNA expression profiling could be used as a tool to understand responses to therapy in human cancers (24,25). We found that 14 miRNAs were upregulated and 12 miRNAs were downregulated by more than 2-fold upon oridonin treatment, primarily representing the let-7 miRNA family and the miR-17-92 paralogous clusters (including the miR-17-92 cluster, miR-106a-363 cluster, and miR-106b-25 cluster), respectively ( Fig.…”

Section: Mirna Expression Profiling Reveals That C-myc Is a Target Ofmentioning

confidence: 99%

Triggering Fbw7-Mediated Proteasomal Degradation of c-Myc by Oridonin Induces Cell Growth Inhibition and Apoptosis

Huang

Weng

Wang

et al. 2012

Molecular Cancer Therapeutics

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The transcription factor c-Myc is important in cell fate decisions and is frequently overexpressed in cancer cells, making it an attractive therapeutic target. Natural compounds are among the current strategies aimed at targeting c-Myc, but their modes of action still need to be characterized. To explore the mechanisms underlying the anticancer activity of a natural diterpenoid, oridonin, we conducted miRNA expression profiling and statistical analyses that strongly suggested that c-Myc was a potential molecular target of oridonin. Furthermore, experimental data showed that oridonin significantly reduced c-Myc protein levels in vitro and in vivo and that this reduction was mediated by the ubiquitin-proteasome system. Fbw7, a component of the ubiquitinproteasome system and an E3 ubiquitin ligase of c-Myc, was upregulated rapidly in K562 cells and other leukemia and lymphoma cells, resulting in the rapid turnover of c-Myc. In cell lines harboring mutations in the WD domain of Fbw7, the degradation of c-Myc induced by oridonin was attenuated during short-term treatment. GSK-3, an Fbw7 priming kinase, was also activated by oridonin, along with an increase in T58-phosphorylated c-Myc. Furthermore, the knockdown of Fbw7 or the forced expression of stable c-Myc resulted in reduced sensitization to oridonin-induced apoptosis. Our observations help to clarify the anticancer mechanisms of oridonin and shed light on the application of this natural compound as an Fbw7-c-Myc pathway targeting agent in cancer treatment.

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“…To assess the potential roles of microRNAs in cancer chemotherapy, we (31) have measured the expression levels of most known microRNAs in 60 human cancer cell lines (the NCI-60) used by the Developmental Therapeutics Program of the National Cancer Institute to screen >100,000 compounds as potential anticancer drug agents (1,32). Analogous molecular profiling of mRNA had previously enabled us to identify the genes involved in drug response by assessing the correlations between mRNA expression levels and the potencies of the tested compounds (for example, see refs.…”

Section: Introductionmentioning

confidence: 99%

MicroRNAs modulate the chemosensitivity of tumor cells

Blower

Chung

Verducci

et al. 2008

Molecular Cancer Therapeutics

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328

229

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MicroRNAs are strongly implicated in such processes as development, carcinogenesis, cell survival, and apoptosis. It is likely, therefore, that they can also modulate sensitivity and resistance to anticancer drugs in substantial ways. To test this hypothesis, we studied the pharmacologic roles of three microRNAs previously implicated in cancer biology (let-7i, mir-16, and mir-21) and also used in silico methods to test pharmacologic microRNA effects more broadly. In the experimental system, we increased the expression of individual microRNAs by transfecting their precursors (which are active) or suppressed the expression by transfection of antisense oligomers. In three NCI-60 human cancer cell lines, a panel of 60 lines used for anticancer drug discovery, we assessed the growthinhibitory potencies of 14 structurally diverse compounds with known anticancer activities. Changing the cellular levels of let-7i, mir-16, and mir-21 affected the potencies of a number of the anticancer agents by up to 4-fold. The effect was most prominent with mir-21, with 10 of 28 cell-compound pairs showing significant shifts in growthinhibitory activity. Varying mir-21 levels changed potencies in opposite directions depending on compound class; indicating that different mechanisms determine toxic and protective effects. In silico comparison of drug potencies with microRNA expression profiles across the entire NCI-60 panel revealed that f30 microRNAs, including mir-21, show highly significant correlations with numerous anticancer agents. Ten of those microRNAs have already been implicated in cancer biology. Our results support a substantial role for microRNAs in anticancer drug response, suggesting novel potential approaches to the improvement of chemotherapy. [Mol Cancer Ther 2008;7(1):1 -9]

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MicroRNA expression profiles for the NCI-60 cancer cell panel

Cited by 225 publications

References 45 publications

Role of the pro-survival molecule Bfl-1 in melanoma

Role of the pro-survival molecule Bfl-1 in melanoma

Triggering Fbw7-Mediated Proteasomal Degradation of c-Myc by Oridonin Induces Cell Growth Inhibition and Apoptosis

MicroRNAs modulate the chemosensitivity of tumor cells

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