Overexpression of RhoA, Rac1, and Cdc42 GTPases Is Associated with Progression in Testicular Cancer

Kamai, Takao; Yamanishi, Tomonori; Shirataki, Hiromichi; Takagi, Kentarô; Asami, Hidekazu; Ito, Yuji; Yoshida, Keisuke

doi:10.1158/1078-0432.ccr-0436-03

Cited by 226 publications

(184 citation statements)

References 29 publications

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“…based on a number of studies, upregulated RhoA is associated with tumor progression in different types of cancer (33)(34)(35) and RhoA activation promotes the migration of cervical, colon and hepatocellular carcinoma (36)(37)(38). However, significantly downregulated expression of RhoA was demonstrated in human conventional RCC compared to that in normal kidney tissues (17) and activated RhoA has specifically been shown to inhibit the migration of breast and prostate cancer (39,40).…”

Section: Discussionmentioning

confidence: 99%

Honokiol inhibits migration of renal cell carcinoma through activation of RhoA/ROCK/MLC signaling pathway

Cheng

Castillo

Welty

et al. 2016

International Journal of Oncology

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Abstract. Honokiol, a biologically active compound isolated from Magnolia bark, has been shown to possess promising anticancer effect through induction of apoptosis. However, there is a relative lack of information regarding its anti-metastatic activity. Renal cell carcinoma (RCC) is the most common malignancy of the adult kidney and is known for high risk of metastasis. Clinically, therapeutic methods for metastatic RCC cases are limited and efforts to exploit new treatments are still ongoing. The results of our current investigation first revealed that honokiol suppressed the proliferation of different human RCCs without affecting cell viability. In addition, honokiol inhibited migration of highly metastatic RCC 786-0 cells and stimulated the activity of small GTPase, RhoA. Furthermore, phosphorylated myosin light chain (MLC) and excessive formation of actin stress fibers were identified in 786-0 cells treated with honokiol. Interestingly, the pharmacological Rho-associated protein kinase (ROCK) inhibitor Y-27632 attenuated contraction of actin stress fibers induced by honokiol and abrogated honokiol-mediated inhibition of cell migration. Together these important findings suggest that honokiol suppresses the migration of highly metastatic RCC through activation of RhoA/ROCK/MLC signaling and warrants attention in the treatment of RCC metastasis as a novel therapeutic approach.

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Section: Discussionmentioning

confidence: 99%

Honokiol inhibits migration of renal cell carcinoma through activation of RhoA/ROCK/MLC signaling pathway

Cheng

Castillo

Welty

et al. 2016

International Journal of Oncology

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“…137,138 The classical Rho GTPases, RhoA, Rac1 and Cdc42, have been shown to be important for the progression and metastasis of different human tumors including breast cancer, liver cancer, melanoma, testicular cancer and ovarian cancer. [139][140][141] RhoA appears to be involved in almost all stages of tumor progression. For example, in gastric cancer cell lines, RhoA is found to be hyperactive and its suppression leads to partial inhibition of the proliferation phenotype.…”

Section: Rho Gtpases In Cancermentioning

confidence: 99%

Rho GTPases: Regulation and roles in cancer cell biology

Haga

Ridley²

2016

Small GTPases

417

390

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Rho GTPases are well known for their roles in regulating cell migration, and also contribute to a variety of other cellular responses. They are subdivided into 2 groups: typical and atypical. The typical Rho family members, including RhoA, Rac1 and Cdc42, cycle between an active GTP-bound and inactive GDP-bound conformation, and are regulated by GEFs, GAPs and GDIs, whereas atypical Rho family members have amino acid substitutions that alter their ability to interact with GTP/GDP and hence are regulated by different mechanisms. Both typical and atypical Rho GTPases contribute to cancer progression. In a few cancers, RhoA or Rac1 are mutated, but in most cancers expression levels and/or activity of Rho GTPases is altered. Rho GTPase signaling could therefore be therapeutically targeted in cancer treatment.

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“…In support of this, preclinical studies have shown beneficial effects of ROCK inhibition on tumor incidence rates, volume, invasiveness and metastasis (Itoh et al, 1999;Somlyo et al, 2000;Nakajima et al, 2003;Ying et al, 2006;Ogawa et al, 2007;Xue et al, 2008). In addition, elevated ROCK1 and/or ROCK2 expression have been detected in several human cancers, which correlated with poor outcome (Kamai et al, 2002(Kamai et al, , 2003(Kamai et al, , 2004Abe et al, 2008). Although alterations in the regulation of ROCK1 signaling as an important contributory factor to human cancer may be well accepted, this is the first report of ROCK1 activation as a direct consequence of somatic mutations.…”

mentioning

confidence: 96%

Activating ROCK1 somatic mutations in human cancer

et al. 2010

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Cancer cells acquire characteristics of deregulated growth, survival and increased metastatic potential. Genetic mutations that provide a selective advantage by promoting these characteristics have been termed 'drivers,' whereas mutations that do not contribute to disease initiation/progression are termed 'passengers.' The advent of high-throughput methodologies has facilitated large-scale screening of cancer genomes and the subsequent identification of novel somatic mutations. Although this approach has generated valuable results, the data remain incomplete until the functional consequences of these mutations are determined to differentiate potential drivers from passengers. ROCK1 is an essential effector kinase downstream of Rho GTPases, an important pathway involved in cell migration. The Cancer Genome Project identified three nonsynonymous mutations in the ROCK1 gene. We now show that these somatic ROCK1 mutations lead to elevated kinase activity and drive actin cytoskeleton rearrangements that promote increased motility and decreased adhesion, characteristics of cancer progression. Mapping of the kinase-interacting regions of the carboxy terminus combined with structural modeling provides an insight into how these mutations likely affect the regulation of ROCK1. Consistent with the frequency of ROCK1 mutations in human cancer, these results support the conclusion that there is selective pressure for the ROCK1 gene to acquire 'driver' mutations that result in kinase activation.

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Overexpression of RhoA, Rac1, and Cdc42 GTPases Is Associated with Progression in Testicular Cancer

Cited by 226 publications

References 29 publications

Honokiol inhibits migration of renal cell carcinoma through activation of RhoA/ROCK/MLC signaling pathway

Honokiol inhibits migration of renal cell carcinoma through activation of RhoA/ROCK/MLC signaling pathway

Rho GTPases: Regulation and roles in cancer cell biology

Activating ROCK1 somatic mutations in human cancer

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