Abstract
The Rho GTPase Cdc42 is highly conserved in structure and function. Mechanical or chemical cues in the microenvironment stimulate the localized activation of Cdc42 to rearrange the actin cytoskeleton and establish cell polarity. A role for Cdc42 in cell polarization was first discovered in the budding yeast Saccharomyces cerevisiae, and subsequently shown to also regulate directional motility in animal cells. Accordingly, in cancer Cdc42 promotes migration, invasion, and spread of tumor cells. Therefore, we targeted Cdc42 as a therapeutic strategy to treat metastatic breast cancer and designed the small molecule MBQ-167 as a potent inhibitor against Cdc42 and the homolog Rac. MBQ-167 inhibited cancer cell proliferation and migration in-vitro, and tumor growth and spread in-vivo in a mouse xenograft model of metastatic breast cancer. Since haploid budding yeast express a single Cdc42 gene, and do not express Rac, we used this well characterized model of polarization to define the contribution of Cdc42 inhibition to the effects of MBQ-167 in eukaryotic cells. Growth, budding pattern, and Cdc42 activity was determined in wildtype yeast or cells expressing a conditional knockdown of Cdc42 in response to vehicle or MBQ-167 treatment. As expected, growth and budding polarity were reduced by knocking-down Cdc42, with a parallel effect observed with MBQ-167. Cdc42 activity assays confirmed that MBQ-167 inhibits Cdc42 activation in yeast, and thus, bud polarity. Hence, we have validated MBQ-167 as a Cdc42 inhibitor in another biological context and present a method to screen Cdc42 inhibitors with potential as anti-metastatic cancer drugs.
Original language | English |
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Pages (from-to) | 430-440 |
Number of pages | 11 |
Journal | Small GTPases |
Volume | 11 |
Issue number | 6 |
DOIs | |
State | Published - Nov 1 2020 |
Bibliographical note
Publisher Copyright:© 2018 Informa UK Limited, trading as Taylor & Francis Group.
Funding
This work is partially supported by grants from the Susan G Komen for the Cure, the Puerto Rico Science and Technology Research Trust, NIH/NIGMS SC3GM084824, NIH/NCI U54 CA096297/09629300 (S.D.), NIH/NIGMS P20GM103475 (JRRM), NIH/NIGMS-RISE R25 GM061838 (MJR), and Linda and Jack Gill Endowment (BR).
Funders | Funder number |
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Linda and Jack Gill Endowment | |
NIGMS-RISE | R25 GM061838 |
National Institutes of Health (NIH) | |
National Childhood Cancer Registry – National Cancer Institute | U54 CA096297/09629300 |
National Childhood Cancer Registry – National Cancer Institute | |
National Institute of General Medical Sciences | P20GM103475, R25GM061838, SC3GM084824 |
National Institute of General Medical Sciences | |
Susan G. Komen for the Cure | |
Puerto Rico Science, Technology and Research Trust |
Keywords
- Cdc42
- Cell polarity
- GTPase inhibition
- MBQ-167
- budding yeast
ASJC Scopus subject areas
- Biochemistry
- Cell Biology