| Title |
A High-Content, Multiplexed Screen in Human Breast Cancer Cells Identifies Profilin-1 Inducers with Anti-Migratory Activities
|
|---|---|
| Published in |
PLOS ONE, February 2014
|
| DOI | 10.1371/journal.pone.0088350 |
| Pubmed ID | |
| Authors |
Marion E. Joy, Laura L. Vollmer, Keren Hulkower, Andrew M. Stern, Cameron K. Peterson, R. C. “Dutch” Boltz, Partha Roy, Andreas Vogt |
| Abstract |
Profilin-1 (Pfn-1) is a ubiquitously expressed actin-binding protein that is essential for normal cell proliferation and migration. In breast cancer and several other adenocarcinomas, Pfn-1 expression is downregulated when compared to normal tissues. Previous studies from our laboratory have shown that genetically modulating Pfn-1 expression significantly impacts proliferation, migration, and invasion of breast cancer cells in vitro, and mammary tumor growth, dissemination, and metastatic colonization in vivo. Therefore, small molecules that can modulate Pfn-1 expression could have therapeutic potential in the treatment of metastatic breast cancer. The overall goal of this study was to perform a multiplexed phenotypic screen to identify compounds that inhibit cell motility through upregulation of Pfn-1. Screening of a test cassette of 1280 compounds with known biological activities on an Oris™ Pro 384 cell migration platform identified several agents that increased Pfn-1 expression greater than two-fold over vehicle controls and exerted anti-migratory effects in the absence of overt cytotoxicity in MDA-MB-231 human breast cancer cells. Concentration-response confirmation and orthogonal follow-up assays identified two bona fide inducers of Pfn-1, purvalanol and tyrphostin A9, that confirmed in single-cell motility assays and Western blot analyses. SiRNA-mediated knockdown of Pfn-1 abrogated the inhibitory effect of tyrphostin A9 on cell migration, suggesting Pfn-1 is mechanistically linked to tyrphostin A9's anti-migratory activity. The data illustrate the utility of the high-content cell motility assay to discover novel targeted anti-migratory agents by integrating functional phenotypic analyses with target-specific readouts in a single assay platform. |
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Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 1 | 100% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 1 | 100% |
Mendeley readers
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Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 1 | 2% |
| Belgium | 1 | 2% |
| Unknown | 47 | 96% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Ph. D. Student | 15 | 31% |
| Student > Bachelor | 9 | 18% |
| Researcher | 8 | 16% |
| Student > Master | 3 | 6% |
| Professor | 1 | 2% |
| Other | 3 | 6% |
| Unknown | 10 | 20% |
| Readers by discipline | Count | As % |
|---|---|---|
| Agricultural and Biological Sciences | 15 | 31% |
| Biochemistry, Genetics and Molecular Biology | 7 | 14% |
| Medicine and Dentistry | 4 | 8% |
| Chemistry | 3 | 6% |
| Engineering | 3 | 6% |
| Other | 6 | 12% |
| Unknown | 11 | 22% |