RhoB Signaling in Cancer Suppression and Cell Suicide

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DESCRIPTION (provided by applicant): Cancer cells overcome apoptotic safeguards that prevent inappropriate cell proliferation, movement, and survival. While great strides have been made in unraveling the basic mechanisms of apoptosis, much less is known about the exact defects in apoptotic signaling that characterize cancer cell pathophysiology. Furthermore, mechanisms of therapeutic cell death in cancer are generally not very well elucidated. Rho proteins are emerging as important players in cancer progression and therapeutic response. These small GTPase of the Ras superfamily, control actin organization but also many other actin-based cellular processes. Genetic investigations in our laboratory have identified the antioncogenic RhoB protein as a key regulator of apoptosis in neoplastic transformed cells. Knockout mouse studies indicate that RhoB is dispensable for physiological apoptosis during development, implying it functions in stress-induced processes. RhoB is not a tumor suppressor, because nullizygous mice do not exhibit a higher incidence of cancer. However, such mice are more prone to tumor formation after they suffer an oncogenic 'hit' (e.g. Ras mutation). Thus, RhoB is a negative modifier gene in cancer, the properties of which are linked to a role in cell death signaling. Preliminary work indicates that RhoB is required to trigger selective apoptosis of transformed cells exposed to farnesyltransferase inhibitors, DNA damaging agents, or paclitaxel. We hypothesize that RhoB activates a p53-independent death pathway that limits cancer and that is recruited by clinically effective cancer therapeutics. We will test this hypothesis in a knockout mouse model system that has been characterized in our laboratory. Specifically, we will (1) define the effect of RhoB loss on tumor susceptibility and therapeutic response in mice, (2) establish the role of RhoB in apoptosis in transformed mouse cells, and (3) investigate the effector mechanisms through which RhoB triggers apoptosis. Our proposal has several innovative elements. We will establish and investigate the function of the RhoB gene, a candidate negative modifier gene in cancer. Modifier genes are of great interest as they strongly affect cancer susceptibility, progression, and therapeutic response. Our notion that cancer drugs may recruit the function of cancer modifier genes is a novel concept. We will study a unique RhoB-dependent and p53- independent cell death mechanism that we have shown to be conditional on transformation status. Lastly, we will test new signaling models that connect Rho to G2/M phase cell cycle events and to a putative cell death regulator that interfaces with actin regulatory systems. Characterization of these signaling pathways offers a unique opportunity to obtain new insights into cancer pathophysiology and therapeutic response.