Targeting Cdc42 with the anticancer compound MBQ-167 inhibits cell polarity and growth in the budding yeast S. cerevisiae

Michael John Rivera-Robles, Julia Medina-Velázquez, Gabriela M. Asencio-Torres, Sahily González-Crespo, Brian C. Rymond, José Rodríguez-Medina, Suranganie Dharmawardhane

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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 languageEnglish
Pages (from-to)430-440
Number of pages11
JournalSmall GTPases
Volume11
Issue number6
DOIs
StatePublished - 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).

FundersFunder number
Linda and Jack Gill Endowment
NIGMS-RISER25 GM061838
National Institutes of Health (NIH)
National Childhood Cancer Registry – National Cancer InstituteU54 CA096297/09629300
National Childhood Cancer Registry – National Cancer Institute
National Institute of General Medical SciencesP20GM103475, 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

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