Abstract
Rho guanosine triphospatases (GTPases) resemble a conserved family of GTP-binding proteins regulating actin cytoskeleton dynamics and several signaling pathways central for the cell. Rho GTPases create a so-called Ras-superfamily of GTPases subdivided into subgroups comprising at least 20 members. Rho GTPases play a key regulatory role in gene expression, cell cycle control and proliferation, epithelial cell polarity, cell migration, survival, and apoptosis, among others. They also have tissue-related functions including angiogenesis being involved in inflammatory and wound healing processes. Contextually, any abnormality in the Rho GTPase function may result in severe consequences at molecular, cellular, and tissue levels. Rho GTPases also play a key role in tumorigenesis and metastatic disease. Corresponding mechanisms include a number of targets such as kinases and scaffold/adaptor-like proteins initiating GTPases-related signaling cascades. The accumulated evidence demonstrates the oncogenic relevance of Rho GTPases for several solid malignancies including breast, liver, bladder, melanoma, testicular, lung, central nervous system (CNS), head and neck, cervical, and ovarian cancers. Furthermore, Rho GTPases play a crucial role in the development of radio- and chemoresistance e.g. under cisplatin-based cancer treatment. This article provides an in-depth overview on the role of Rho GTPases in gynecological cancers, highlights relevant signaling pathways and pathomechanisms, and sheds light on their involvement in tumor progression, metastatic spread, and radio/chemo resistance. In addition, insights into a spectrum of novel biomarkers and innovative approaches based on the paradigm shift from reactive to predictive, preventive, and personalized medicine are provided.
Highlights
Deregulation of the Rho guanosine triphospatases (GTPases) function is involved in various pathological processes including tumorigenesis (Figure 2) [10]
Zaoui et al [60] found out that on plasma membrane (PM) RhoA GTPase formed a complex with another small GTPase nucleocytoplasmic shuttle protein Ras-related nuclear protein (Ran) [63], which is strongly associated with Epithelial ovarian cancer (EOC) progression and poor overall survival [64]
This review provides the link between Rho GTPases signaling pathways that collectively contribute to biologic and pathologic mechanisms involved in gynecologic cancers at the level of cancer cell growth, invasiveness, metastatic spreading, and therapeutic response
Summary
Rho guanosine triphospatases (GTPases) are small signaling, GTP binding proteins forming a family of the Ras superfamily. (Cdc, RhoJ, RhoQ), Rac (Rac, Rac, Rac, RhoG), RhoUV (RhoU, RhoV), Rho (RhoA, RhoB, RhoC), RhoBTB (RhoBTB1, RhoBTB2), RhoDF (RhoD, RhoF), RhoH (RhoH1), and Rnd (Rnd, Rnd, Rnd3) [4] (Figure 1) Based on their structure and regulation mechanism of their enzymatic activity, Rho GTPases are classified as typical and atypical [5,6]. Rho GTPases are part of signal cascades with roles in the regulation of various cellular processes, mainly cytoskeletal organization and dynamics, cell shape, polarity, motility, vesicular trafficking, cell division, gene expression, and others [8] They are activated in response to extracellular stimuli in the form of soluble molecules, adhesive interactions or mechanical stresses. Disequilibrium of GTPases has a significant impact on the carcinogenesis
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