Rac1 expression in epithelial ovarian cancer: effect on cell EMT and clinical outcome

Leng, Ruobing; Liao, Gang; Wang, Haixia; Kuang, Jun; Tang, Liangdan

doi:10.1007/s12032-014-0329-5

Cited by 49 publications

(64 citation statements)

References 36 publications

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“…Rac1 is abnormally expressed and activated in stomach and ovarian cancers. The high expression of Rac1 is positively correlated with highly invasive cancer and poor prognosis 17, 18, 25. We found that Rac1 was significantly expressed in lung cancer tissues, and was positively correlated with TNM stage, metastasis and poor prognosis, which was consistent with Yuan K's report 26.…”

Section: Discussionsupporting

confidence: 90%

“…Reduced E-cadherin expression increases the expression of Vimentin, N-cadherin, Snail1, and Twist1. The study showed that high expression of Rac1 induced EMT in tumor cells in vitro and in vivo 17, 18, and promoted invasion and metastasis of tumor. The inhibition of Rac1 expression significantly up-regulated the expression of E-cadherin, down-regulated the expression of N-cadherin and Vimentin, and significantly inhibited EMT in cancer cells 21.…”

Section: Discussionmentioning

confidence: 98%

“…Rac1 is over-expressed in many tumors, and is closely associated with tumor invasion 17. The Rac1 expression level is positively correlated with tumor progression, metastases and poor prognosis of specific carcinomas 18. Inhibition of Rac1 expression or disruption of its function may significantly inhibit cancer cell proliferation and metastasis 17, 19.…”

Section: Introductionmentioning

confidence: 99%

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Rac1 overexpression is correlated with epithelial mesenchymal transition and predicts poor prognosis in non-small cell lung cancer

Zhou¹,

Liao²,

Han³

et al. 2016

J. Cancer

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Objective: Ras-related C3 botulinum toxin substrate1(Rac1) and epithelial mesenchymal transition (EMT) are key therapeutic targets in cancer. We investigated the clinical significance of Rac1 and markers of EMT expression in non-small cell lung cancer (NSCLC), and their possible correlation with EMT phenotype.Methods: Immunohistochemistry was used to assess the expression of Rac1, Snail1, Twist1, N-cadherin (N-cad), Vimentin (Vim), and E-cadherin (E-cad) in 153 NSCLC paraffin-embedded specimens and 45 normal specimens adjacent to tumors. The correlation of Rac1 and EMT markers with clinicopathological characteristics and the relationship between the protein levels and progression-free survival (PFS) and overall survival (OS) were analyzed.Results: Compared with non-tumor tissues, the NSCLC tissues showed marked elevation in the levels of Rac1, Snail1, Twist1, N-cad, and Vim levels, whereas the E-cad levels were significantly decreased (P < 0.05). The aberrant expression of Rac1 and EMT markers was significantly associated with TNM stage and metastasis (P < 0.05). Increased expression of Rac1 may be associated with poor OS and PFS compared with low expression (P<0.001 and P=0.004). Significant correlations were observed between the EMT markers expressed and OS or PFS(P<0.01). In addition, multivariate analysis indicated that the expression of Rac1, Snail1, Twist1, N-cad, Vim, and E-cad was an independent prognostic factor in NSCLC. Interestingly, Rac1 expression was positively correlated with Snail1, Twist1, N-cad, and Vim levels (r=0.563, r=0.440, r=0.247 r=0.536, P<0.01, respectively) and negatively correlated with E-cad levels (r=-0.464, P<0.001) in NSCLC tissues. Rac1, Twist, Snail1, Vim and N-cad were highly expressed in lung cancer patients resistant to radiotherapy, while E-cad was poorly expressed.Conclusion: Rac1 may promote NSCLC progression and metastasis via EMT, which may be considered as a potential therapeutic target.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Rac1 overexpression is correlated with epithelial mesenchymal transition and predicts poor prognosis in non-small cell lung cancer

Zhou¹,

Liao²,

Han³

et al. 2016

J. Cancer

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“…Z-scores were used to account for large differences in absolute GTPase activity levels observed for individual patient samples (Fig. 2C, 2D), likely related to known differences in GTPase overexpression seen in ovarian cancer (11, 12). The inhibitory effect of R-ketorolac in primary ovarian cancer cells is consistent with the observations in SKOV3ip cells.…”

Section: Resultsmentioning

confidence: 99%

R-Ketorolac Targets Cdc42 and Rac1 and Alters Ovarian Cancer Cell Behaviors Critical for Invasion and Metastasis

Guo

Kenney

Muller

et al. 2015

Molecular Cancer Therapeutics

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Cdc42 (cell division control protein 42) and Rac1 (Ras-related C3 botulinum toxin substrate 1) are attractive therapeutic targets in ovarian cancer based on established importance in tumor cell migration, adhesion and invasion. Despite a predicted benefit, targeting GTPases has not yet been translated to clinical practice. We previously established that Cdc42 and constitutively active Rac1b are overexpressed in primary ovarian tumor tissues. Through high throughput screening and computational shape homology approaches we identified R-ketorolac as a Cdc42 and Rac1 inhibitor; distinct from the anti-inflammatory, cyclooxygenase inhibitory activity of S-ketorolac. In the present study, we establish R-ketorolac as an allosteric inhibitor of Cdc42 and Rac1. Cell-based assays validate R-ketorolac activity against Cdc42 and Rac1. Studies on immortalized human ovarian adenocarcinoma cells (SKOV3ip), and primary, patient-derived ovarian cancer cells show R-ketorolac is a robust inhibitor of growth factor or serum dependent Cdc42 and Rac1 activation with a potency and cellular efficacy similar to small molecule inhibitors of Cdc42 (CID2950007/ML141) and Rac1 (NSC23766). Furthermore, GTPase inhibition by R-ketorolac reduces downstream p21-activated kinases (PAK1/PAK2) effector activation by >80%. Multiple assays of cell behavior using SKOV3ip and primary patient-derived ovarian cancer cells show that R-ketorolac significantly inhibits cell adhesion, migration and invasion. In sum, we provide evidence for R-ketorolac as direct inhibitor of Cdc42 and Rac1 that is capable of modulating downstream GTPase-dependent, physiological responses, which are critical to tumor metastasis. Our findings demonstrate the selective inhibition of Cdc42 and Rac1 GTPases by an FDA approved drug-racemic ketorolac that can be used in humans.

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“…Additionally, ascites have been shown to enhance epithelial to mesenchymal transition (EMT) in ovarian cancer cells. 8,41,42 During EMT, a stationary epithelial cell transforms into a mesenchymal cell capable of motility. This transition is an important precursor for metastasis and chemoresistance.…”

Section: A the Ovarian Cancer Mechanical Microenvironmentmentioning

confidence: 99%

Review: Mechanotransduction in ovarian cancer: Shearing into the unknown

2018

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Perspective: The role of mechanobiology in the etiology of brain metastasis APL Bioengineering 2, 031801 (2018) Ovarian cancer remains a deadly diagnosis with an 85% recurrence rate and a 5-year survival rate of only 46%. The poor outlook of this disease has improved little over the past 50 years owing to the lack of early detection, chemoresistance and the complex tumor microenvironment. Within the peritoneal cavity, the presence of ascites stimulates ovarian tumors with shear stresses. The stiff environment found within the tumor extracellular matrix and the peritoneal membrane are also implicated in the metastatic potential and epithelial to mesenchymal transition (EMT) of ovarian cancer. Though these mechanical cues remain highly relevant to the understanding and treatment of ovarian cancers, our current knowledge of their biological processes and their clinical relevance is deeply lacking. Seminal studies on ovarian cancer mechanotransduction have demonstrated close ties between mechanotransduction and ovarian cancer chemoresistance, EMT, enhanced cancer stem cell populations, and metastasis. This review summarizes our current understanding of ovarian cancer mechanotransduction and the gaps in knowledge that exist. Future investigations on ovarian cancer mechanotransduction will greatly improve clinical outcomes via systematic studies that determine shear stress magnitude and its influence on ovarian cancer progression, metastasis, and treatment.

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Rac1 expression in epithelial ovarian cancer: effect on cell EMT and clinical outcome

Cited by 49 publications

References 36 publications

Rac1 overexpression is correlated with epithelial mesenchymal transition and predicts poor prognosis in non-small cell lung cancer

Rac1 overexpression is correlated with epithelial mesenchymal transition and predicts poor prognosis in non-small cell lung cancer

R-Ketorolac Targets Cdc42 and Rac1 and Alters Ovarian Cancer Cell Behaviors Critical for Invasion and Metastasis

Review: Mechanotransduction in ovarian cancer: Shearing into the unknown

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