Given that most cancer patients die from metastatic disease, there is an urgent need to develop drugs that inhibit the spread of tumors. Studies show that the motuporamines activate the small GTPase RhoA to prevent cancer cell migration, but little is known about the mechanism of action of dihydromotuporamine C (Motu33) and its synthetic derivative Motu-(CH2)-33. In the present study, I investigated the biomolecular processes of these compounds in Drosophila by reducing the gene dose of positive and negative regulators of actin dynamics. Consistent with previous findings, reduced gene dose of Rho1 (the Drosophila RhoA ortholog) attenuates motuporamine activity confirming that RhoA/Rho1 are targeted by these compounds. Actin-myosin contraction is controlled by the Rho1-ROCK-myosin regulatory light chain (MRLC) pathway. Reduced gene dose of the myosin binding subunit of myosin phosphatase, which is a negative regulator of the Rho1-ROCK-MRLC pathway, encourages motuporamine activity indicating that the motuporamines stimulate actin-myosin contraction. Rho1 also activates diaphanous (dia) to control actin polymerization. Surprisingly, reduced gene dose of dia facilitates motuporamine activity suggesting that the motuporamines act on dia in a Rho1-independent manner. Reduction in gene dose of the Drosophila Rac orthologs Rac1 and Mtl enhances motuporamine activity. In contrast, motuporamine activity is unaffected by reduced gene dose of slingshot (ssh) which acts to trigger actin severing and depolymerization. Since ssh is directly regulated by Rac1, the enhanced activity of motuporamines under reduced Rac1 and Mtl gene dose may reflect an indirect mode of action on the Rac GTPases leading to increased Rho1 activity. In all, these findings indicate that motuporamines act through Rho1 and diaphanous to regulate actin-myosin contractility and actin polymerization and may be a promising novel therapy to deter cancer cell migration.
| Identifer | oai:union.ndltd.org:ucf.edu/oai:stars.library.ucf.edu:etd2020-2154 |
| Date | 01 January 2021 |
| Creators | Seavey, Corey |
| Publisher | STARS |
| Source Sets | University of Central Florida |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Electronic Theses and Dissertations, 2020- |
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