A Rac1/Cdc42 GTPase-Specific Small Molecule Inhibitor Suppresses Growth of Primary Human Prostate Cancer Xenografts and Prolongs Survival in Mice

Zins, Karin; Lucas, Trevor; Reichl, Patrick; Abraham, Dietmar; Aharinejad, Seyedhossein

doi:10.1371/journal.pone.0074924

Cited by 84 publications

(73 citation statements)

References 62 publications

(82 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…2,27 Our data indicate that a simultaneous inhibition of both Cdc42 and Rac1 would likely have a more profound effect on lymphoma growth and dissemination. As dual Cdc42/Rac1 inhibitors have been recently developed and are currently tested in preclinical mouse models, 28 this approach could represent a potential additional therapeutic strategy for NPM-ALK lymphoma. …”

Section: Discussionmentioning

confidence: 99%

Redundant and nonredundant roles for Cdc42 and Rac1 in lymphomas developed in NPM-ALK transgenic mice

Choudhari

Minero

Menotti

et al. 2016

Blood

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

Redundant and nonredundant roles for Cdc42 and Rac1 in lymphomas developed in NPM-ALK transgenic mice

Choudhari

Minero

Menotti

et al. 2016

Blood

View full text Add to dashboard Cite

show abstract

“…Compared with FAK inhibitors, Rac1 inhibitors were under development. 35,36 Hopefully, the development of these inhibitors may provide us a new therapeutic option for both efficacious and nontoxic treatment of OSCC in the near future. In summary, we have demonstrated the elevated FAK expression and its pY397 in OSCC tumors and cell lines.…”

mentioning

confidence: 99%

Tyrosine 397 phosphorylation is critical for FAK-promoted Rac1 activation and invasive properties in oral squamous cell carcinoma cells

Yuan

2016

Laboratory Investigation

View full text Add to dashboard Cite

Oral squamous cell carcinoma (OSCC) is a common cancer worldwide. Despite advances in diagnosis and therapy, treatment options for patients with metastatic OSCC are few, due in part to the limited understanding of the molecular events involved in the invasion and metastasis of OSCC. In this study, we investigated the expression of focal adhesion kinase (FAK) and its tyrosine 397 phosphorylation (pY397) in the tissue specimens of OSCC. The roles of pY397 in regulating the activities of Rac1 and cortactin and the invasive properties of OSCC cells were further determined. Results from immunohistochemical analyses in 9 benign, 19 premalignant, and 19 malignant oral tissues showed that the immunoreactivity of FAK was observed in 5 benign (56%), 19 premalignant (100%), and 18 malignant tissues (95%), whereas the immunoreactivity of pY397 was only found in 1 of 9 (11%) benign lesions but was observed in 9 premalignant (47%) and 12 malignant (63%) lesions. Compared with the low-invading SCC4 cells, the high-invading OECM-1 cells exhibited higher levels of FAK expression and pY397, correlating with higher levels of GTP-bound Rac1 and cortactin phosphorylation. Manipulation of FAK expression or Y397 phosphorylation in SCC4, FaDu, OECM-1, or HSC-3 cells regulated their Rac1 activities and invasive properties. Furthermore, treatment of NSC23766, a Rac1-specific inhibitor, in OECM-1 and HSC-3 cells led to reduced invasive properties. Nevertheless, knockdown of FAK expression or suppression of pY397 had no effect on the cortactin activity in OECM-1 cells. The data collectively suggest that pY397 plays critical roles in the FAK-promoted Rac1 activation and invasive properties in OSCC cells. Thus, the inhibition of FAK phosphorylation at Y397 or Rac1 activity can serve as a therapeutic strategy for treating patients with metastatic OSCC. Oral squamous cell carcinoma (OSCC) is the most common malignancy occurring in the oral cavity that usually arises from the buccal mucosa and tongue. During the tumor progression, OSCC cells gradually spread and invade to neighboring tissues, including the nasal cavity or the maxillary facial structures, and eventually metastasize to neck lymph nodes and distant organs. 1 Similar to other malignant diseases, tumor metastasis is a great challenge for the treatment of OSCC. This notion is supported by the fact that only 50% of diagnosed OSCC patients can survive for 5 years, and this is mainly because OSCC patients continue to die from tumor relapse at regional or distant sites. 2 Despite advances in diagnosis and therapy in past decades, the promising strategy for treating patients with metastatic OSCC is still underdeveloped, due in part to the limited understanding of the molecular events involved in invasion and metastasis of OSCC. The underlying molecular basis of OSCC metastasis deserves intensive study.Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase and functionally involves the regulatory processes of multiple cellular events, including adhesion, migration, invasion, prolifer...

show abstract

“…More recently, the vital role of Cdc42 in the regulation of cancer cell proliferation, migration and invasion has been gradually revealed, and Cdc42 may become a promising target for the treatment of cancer (13,20). In a study by Zins et al (21) it was demonstrated that a Ras-related C3 botulinum toxin substrate 1/Cdc42 GTPase-specific small molecule inhibitor could effectively suppress the growth of primary human prostate cancer xenografts and prolong survival in mice. Furthermore, it has been reported that Cdc42 expression is significantly upregulated in bladder cancer tissues compared with that in normal tissues, and Cdc42 silencing caused by siRNA can inhibit the phosphorylation of STAT3 and suppress the growth of bladder cancer cells, suggesting that Cdc42 may serve as a therapeutic target for the treatment of bladder cancer (22,14).…”

mentioning

confidence: 99%

microRNA-195 inhibits cell proliferation in bladder cancer via inhibition of cell division control protein 42 homolog/signal transducer and activator of transcription-3 signaling

Zhao¹,

Lin²,

Chen³

et al. 2015

Experimental and Therapeutic Medicine

View full text Add to dashboard Cite

Abstract. microRNA (miR)-195 acts as a suppressor in multiple types of malignant tumors, including bladder cancer; however, the detailed function of miR-195 in bladder cancer remains largely unknown. The aim of the present study was to investigate the role of miR-195 in the regulation of bladder cancer cell proliferation and to determine whether cell division control protein 42 homolog (Cdc42)/signal transducer and activator of transcription-3 (STAT3) signaling acts as a downstream effector of miR-195 in bladder cancer cells. Reverse transcription-quantitative polymerase chain reaction was used to determine the expression levels of miR-195 in bladder cancer tissues and normal adjacent tissue. The results revealed that the expression of miR-195 was significantly downregulated in bladder cancer tissues compared with that in the normal adjacent tissues. A luciferase reporter assay was then conducted, which identified Cdc42 as a direct target of miR-195, and the expression of Cdc42 was significantly upregulated in bladder cancer tissues, as determined by western blotting. Furthermore, miR-195 negatively regulated the protein expression of Cdc42 in bladder cancer cells. An MTT assay was also conducted to determine the rate of cell proliferation. Upregulation of miR-195 or the inhibition of Cdc42 could inhibit bladder cancer cell proliferation, possibly through activation of STAT3 signaling. In addition, restoration of Cdc42 could reverse the inhibitory effect of miR-195 upregulation on bladder cancer cell proliferation. In conclusion, the results of the present study suggest that miR-195 plays an inhibitory role in the regulation of bladder cancer cell proliferation by directly targeting Cdc42/STAT3 signaling.

show abstract

A Rac1/Cdc42 GTPase-Specific Small Molecule Inhibitor Suppresses Growth of Primary Human Prostate Cancer Xenografts and Prolongs Survival in Mice

Cited by 84 publications

References 62 publications

Redundant and nonredundant roles for Cdc42 and Rac1 in lymphomas developed in NPM-ALK transgenic mice

Redundant and nonredundant roles for Cdc42 and Rac1 in lymphomas developed in NPM-ALK transgenic mice

Tyrosine 397 phosphorylation is critical for FAK-promoted Rac1 activation and invasive properties in oral squamous cell carcinoma cells

microRNA-195 inhibits cell proliferation in bladder cancer via inhibition of cell division control protein 42 homolog/signal transducer and activator of transcription-3 signaling

Contact Info

Product

Resources

About