Today's open access paper is a good introduction to what makes the Rho-GTPase family an important area of study in molecular biochemistry: it is relevant to efforts to suppress cancer metastasis. If metastasis could be eliminated, the majority of cancer mortality would evaporate, even if no further advances occurred in the field. Surgical techniques would be sufficient to remove most tumors even at later stages. Cancer would become a localized problem in the body, much less of a threat.
Unfortunately, while the biochemistry of metastasis is quite well understood, satisfactory efforts to interfere have yet to emerge. As is so often the case in cell biology, the runaway mechanisms involved in the migration and attachment of cancer cells are also essential to normal tissue function. One can't just break the mechanism for benefit, as that generates serious side-effects, too serious for even cancer patients. So, as illustrated by this paper, one has to approach the target mechanism in a better, more indirectly.
Tumour cells disseminate by migration, either collectively as sheets and clusters, or individually, where single cells transition through a mesenchymal- and/or amoeboid type of migration to escape from the primary tumour and invade target organs to establish new connective attachments, followed by unrestrained growth and proliferation. Single and collective cell migration, both share common pathways of receptor-mediated stimulation that are tightly regulated via signalling cascades involving members of the Ras homologous (Rho) family of small guanosine triphosphatases (GTPases), including Rho, Rac, and Cdc42.
Aberrant RhoGTPase signalling is considered a dominant driving force of metastasis and cancer progression. Particularly, oncogenic mutations in RhoGTPases and their regulators, excessive receptor signalling, and altered effector activity patterns, are factors that stimulate cells to gain pro-migratory capabilities and acquire highly invasive, proliferative phenotypes that promote dissemination and metastasis formation. Thus, targeted interference of Rho-associated signalling cues has become a viable and increasingly investigated strategy for suppressing cancer metastasis. Lack of target selectivity, side effects, and development of resistances have yet prevented positive responses to treatments and therapeutic breakthroughs.
A promising, yet elusively explored approach to target the metastatic properties of cancer cells, particularly those related to enhanced migration and invasiveness, is to gain control over the activity of GTPase-activating proteins (GAPs), the negative regulators of RhoGTPases. Drugs that are capable of enhancing and/or locally controlling RhoGAP activity provide a means to suppress the adhesive and migratory properties of cancer cells, and thus metastasis.
Here, we report the identification and characterization of adhibin, a synthetic allosteric inhibitor of RhoGAP class-IX myosins that abrogates ATPase and motor function, suppressing RhoGTPase-mediated modes of cancer cell metastasis. In human and murine adenocarcinoma and melanoma cell models, including three-dimensional spheroid cultures, we reveal anti-migratory and anti-adhesive properties of adhibin, affecting actin-dynamics and actomyosin-based cell-contractility. Adhibin blocks membrane protrusion formation, disturbs remodelling of cell-matrix adhesions, affects contractile ring formation, and disrupts epithelial junction stability; processes severely impairing single/collective cell migration and cytokinesis.
View the full article at FightAging
