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

4 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.

Keywords

  • Cdc42
  • Cell polarity
  • GTPase inhibition
  • MBQ-167
  • budding yeast

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

Fingerprint

Dive into the research topics of 'Targeting Cdc42 with the anticancer compound MBQ-167 inhibits cell polarity and growth in the budding yeast S. cerevisiae'. Together they form a unique fingerprint.

Cite this