Active RAC1 Promotes Tumorigenic Phenotypes and Therapy Resistance in Solid Tumors

Abstract

Acting as molecular switches, all three members of the Guanosine triphosphate (GTP)-ase-family, Ras-related C3 botulinum toxin substrate (RAC), Rho, and Cdc42 contribute to various processes of oncogenic transformations in several solid tumors. We have reviewed the distribution of patterns regarding the frequency of Ras-related C3 botulinum toxin substrate 1 (RAC1)-alteration(s) and their modes of actions in various cancers. The RAC1 hyperactivation/copy-number gain is one of the frequently observed features in various solid tumors. We argued that RAC1 plays a critical role in the progression of tumors and the development of resistance to various therapeutic modalities applied in the clinic. With this perspective, here we interrogated multiple functions of RAC1 in solid tumors pertaining to the progression of tumors and the development of resistance with a special emphasis on different tumor cell phenotypes, including the inhibition of apoptosis and increase in the proliferation, epithelial-to-mesenchymal transition (EMT), stemness, pro-angiogenic, and metastatic phenotypes. Our review focuses on the role of RAC1 in adult solid-tumors and summarizes the contextual mechanisms of RAC1 involvement in the development of resistance to cancer therapies.

Rac1 as a Target to Treat Dysfunctions and Cancer of the Bladder

“…The list of pathologies addressable with Rac1 inhibitors has expanded significantly in recent years to include diabetes, neurodevelopmental disorders, pulmonary hypertension, asthma and other pathologies [ 25 , 128 , 129 , 130 , 131 ]. In cancer, Rac1 is receiving more and more attention given the large implications of the protein in metastasis, drug resistance and immune modulation [ 43 , 46 , 132 ]. Our analysis indicates that Rac1 plays a significant role in several bladder dysfunctions and can be considered a target in three pathologic situations: bacterial infections of the bladder, diabetes-induced bladder diseases and bladder cancer.…”

STEAP3 promotes cancer cell proliferation by facilitating nuclear trafficking of EGFR to enhance RAC1-ERK-STAT3 signaling in hepatocellular carcinoma

“…RAC1, a member of the Rho family of small GTPases that acts as molecular switch through GDP-bound inactive and GTP-bound active states and regulates a wide range of cellular processes, including cell proliferation, differentiation, survival, motility, nuclear and cytoskeleton assembly, was recently reported that its nuclear translocation associates with carcinogenesis and enhanced aggressiveness of cancer. As a signaling hub integrating receptor-associated intracellular signaling into dynamic cellular response, RAC1 has been shown to be a critical component of EGFR signaling in various tumors and implicated in regulating ERK/JNK signaling [ 47 , 48 ]. EGFR stimulated ERK activation phosphorylates RAC1 on Thr108 and targets RAC1 for nuclear translocation [ 49 ].…”

RAC1B Regulation of TGFB1 Reveals an Unexpected Role of Autocrine TGFβ1 in the Suppression of Cell Motility

“…A prototype example is RAC1, a gene that gives rise to two splice isoforms, RAC1 and RAC1B, belonging to the Rho family of small GTPases. RAC1 is a known driver of oncogenic transformation, tumor progression and chemoresistance of various solid cancers, in part through promoting non-Smad-dependent TGFβ signaling [12]. Likewise, RAC1B has been demonstrated to drive growth of colorectal, pancreatic, lung and thyroid carcinomas via its ability to promote cell cycle progression, apoptosis resistance, or escape from oncogene-induced senescence (reviewed in [13].…”