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| Status |
Public on Aug 15, 2015 |
| Title |
Annexin A6-mediated tumor suppression requires inhibition of calcium influx and down-regulation of the calcium-activated RasGRF2 |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Membrane association of the tumor suppressor, annexin A6 (AnxA6), has been shown to regulate plasma membrane permeability to extracellular Ca2+, inhibit anchorage-independent tumor cell growth and paradoxically, promote tumor cell motility by mechanisms that remains poorly understood. Here, we identified RasGRF2, a Ca2+-activated Ras-specific guanine nucleotide exchange factor, as a major effector of AnxA6-elicited tumor-associated phenotypes in breast cancer cells. We demonstrate that reduced expression or loss of AnxA6 in breast cancer cells is associated with up-regulation of RasGRF2, increased Ras activity and consequently, early onset and rapid growth of xenograft tumors. Meanwhile, up-regulation of AnxA6 in AnxA6-low breast cancer cells is associated with a decrease in Ras activity and growth of xenograft tumors but on the contrary, an increase in Cdc42 activity and EGF-stimulated cell motility. Inhibition of Ca2+ influx into AnxA6-low breast cancer cells via Ni2+-sensitive or non-selective Ca2+ channels dose-dependently suppressed the expression of RasGRF2, induced the expression of AnxA6 and consequently, inhibited tumor cell proliferation. Finally, aberrant expression of RasGRF2 may be triggered by AnxA6-mediated or pharmacological inhibition of non-selective Ca2+ channels and occurs at least in part, by promoter methylation. These data for the first time identify RasGRF2 as a major effector of AnxA6-dependent breast tumor growth and motility and that regulated Ca2+ influx and/or RasGRF2 may be potential therapeutic targets for rapidly growing AnxA6-low breast carcinomas
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| Overall design |
Four replicates of cell lines generated by stable transfection of control and two distinct shRNAs targeting annexin A6 in the mesencymal-like BT-549 breast cancer cell line
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| Contributor(s) |
Sakwe A, LeBlanc J |
| Citation(s) |
30719209 |
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| Submission date |
Aug 14, 2015 |
| Last update date |
Mar 15, 2019 |
| Contact name |
Amos M Sakwe |
| E-mail(s) |
asakwe@mmc.edu
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| Phone |
6153276064
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| Organization name |
Meharry Medical Colle
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| Department |
Biochemistry and Cancer Biology/SOGSR
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| Lab |
WBS Bldg, Room 3108
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| Street address |
1005 Dr. DB Todd Jr Blvd
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| City |
Nashville |
| State/province |
TN |
| ZIP/Postal code |
37208 |
| Country |
USA |
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| Platforms (1) |
| GPL16686 |
[HuGene-2_0-st] Affymetrix Human Gene 2.0 ST Array [transcript (gene) version] |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA292905 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE72083_RAW.tar |
98.6 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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