Pharmacological inhibition of Rac1-PAK1 axis restores tamoxifen sensitivity in human resistant breast cancer cells

González, Nazareno; Cardama, Georgina Alexandra; Comin, Maria Julieta; Segatori, Valeria Inés; Pífano, Marina; Alonso, Daniel F.; Gomez, Daniel E.; Menna, Pablo Lorenzano

doi:10.1016/j.cellsig.2016.12.002

Cited by 33 publications

(31 citation statements)

References 48 publications

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“…1A-116 ( Figure 1A) is a small compound previously described by our group that was developed by a rational design approach using in silico virtual screening. In previous reports, we showed that 1A-116 was able to inhibit Rac1-GEF interactions reducing Rac1 activation levels and showing anti-proliferative effects on different cancer cell lines ( Figure 1B; Cardama et al, 2014a,b;Cabrera et al, 2017;Gonzalez et al, 2017) but not in COS-1 cells used in the luciferase assays ( Figure 1C). The drug-likeness of this small molecule compound meets Lipinski's rules for small molecule drugs (Lipinski et al, 2001;Lipinski, 2004).…”

Section: Drug-like Properties Of 1a-116mentioning

confidence: 56%

“…Given the high attrition rates in drug discovery, it is of great interest having a deep understanding of drug activities before exploring the clinical benefit of these molecules. Here, we provide data regarding the pharmacology of the Rac1 inhibitor, 1A-116, a small molecule developed by our group that has already shown promising preclinical performance (Cardama et al, 2014a,b;Cabrera et al, 2017;Gonzalez et al, 2017). For this purpose, we conducted an interdisciplinary approach taking advantage of bioinformatics, confirming this information with in vitro testing and finally, analyzing different events in cell-based assays where Rac1 plays a vital role.…”

Section: Discussionmentioning

confidence: 93%

“…In fact, it is highly conserved in other members of the Rho GTPase family of proteins, such as Rac2/3 and RhoA/B/C/D/G (Haeusler et al, 2003). 1A-116 Rac1 inhibitor showed antitumoral activity in vitro on a wide variety of cancer types such as breast cancer (Cardama et al, 2014a;Gonzalez et al, 2017), glioblastoma (Cardama et al, 2014b) and acute myeloid leukemia (Cabrera et al, 2017). In this regard, we have already reported that 1A-116 has a profound effect on proliferation, migration, invasion, metastasis, apoptosis, and cell cycle arrest.…”

Section: Introductionmentioning

confidence: 99%

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Computational and in vitro Pharmacodynamics Characterization of 1A-116 Rac1 Inhibitor: Relevance of Trp56 in Its Biological Activity

González

Cardama

Chinestrad

et al. 2020

Front. Cell Dev. Biol.

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In the last years, the development of new drugs in oncology has evolved notably. In particular, drug development has shifted from empirical screening of active cytotoxic compounds to molecularly targeted drugs blocking specific biologic pathways that drive cancer progression and metastasis. Using a rational design approach, our group has developed 1A-116 as a promising Rac1 inhibitor, with antitumoral and antimetastatic effects in several types of cancer. Rac1 is over activated in a wide range of tumor types and and it is one of the most studied proteins of the Rho GTPase family. Its role in actin cytoskeleton reorganization has effects on endocytosis, vesicular trafficking, cell cycle progression and cellular migration. In this context, the regulatory activity of Rac1 affects several key processes in the course of the cancer including invasion and metastasis. The purpose of this preclinical study was to focus on the mode of action of 1A-116, conducting an interdisciplinary approach with in silico bioinformatics tools and in vitro assays. Here, we demonstrate that the tryptophan 56 residue is necessary for the inhibitory effects of 1A-116 since this compound interferes with protein-protein interactions (PPI) of Rac1GTPase involving several GEF activators. 1A-116 is also able to inhibit the oncogenic Rac1 P29S mutant protein, one of the oncogenic drivers found in sun-exposed melanoma. It also inhibits numerous Rac1-regulated cellular processes such as membrane ruffling and lamellipodia formation. These results deepen our knowledge of 1A-116 inhibition of Rac1 and its biological impact on cancer progression. They also represent a good example of how in silico analyses represent a valuable approach for drug development.

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Section: Drug-like Properties Of 1a-116mentioning

confidence: 56%

Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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Computational and in vitro Pharmacodynamics Characterization of 1A-116 Rac1 Inhibitor: Relevance of Trp56 in Its Biological Activity

González

Cardama

Chinestrad

et al. 2020

Front. Cell Dev. Biol.

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“…Studies revealed that activation of RAC1/PAK1 pathway enhanced ovarian cancer metastasis (Fan, ). Oppositely, blocking RAC1/PAK1 axis could increase sensitivity of resistant BC cells to tamoxifen (Gonzalez et al, ). Our results manifested that RAC1 downregulation resulted from overexpressed miR‐142‐3p significantly downregulated the level of PAK1 phophorylation.…”

Section: Discussionmentioning

confidence: 99%

MiR‐142‐3p functions as a tumor suppressor by targeting RAC1/PAK1 pathway in breast cancer

Pan

et al. 2019

Journal Cellular Physiology

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MicroRNA -142-3p (miR-142-3p) was previously investigated in various cancers, whereas, itʼs role in breast cancer (BC) remains far from understood. In this study, we found that miR-142-3p was markedly decreased both in cell lines and BC tumor tissues. Elevated miR-142-3p expression suppressed growth and metastasis of BC cell lines via gain-of-function assay in vitro and in vivo. Mechanistically, miR-142-3p could regulate the ras-related C3 botulinum toxin substrate 1 (RAC1) expression in protein level, which simultaneously suppressed the epithelial-to-mesenchymal transition related protein levels and the activity of PAK1 phosphorylation, respectively. In addition, rescue experiments revealed RAC1 overexpression could reverse tumorsuppressive role of miR-142-3p. Our results showed miR-142-3p could function as a tumor suppressor via targeting RAC1/PAK1 pathway in BC, suggesting a potent therapeutic target for BC treatment. K E Y W O R D Sbreast cancer, miR-142-3p, PAK1, RAC1

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“…This effect is likely mediated by Rac activation of its main downstream effector, Pak1, which has been involved in tamoxifen resistance by promoting the phosphorylation of ER at Ser305, resulting in increased cyclin D1 expression. Notably, pharmacological inhibition of Rac1 restores the anti-proliferative effects of tamoxifen by reducing ER Ser305 phosphorylation (59). Similarly, Rac1 activity has been associated with resistance of ErbB2/HER2-positive breast cancer patients to the monoclonal antibody trastuzumab.…”

Section: Targeting Rac Gtpases: Can We Overcome Therapy Resistance?mentioning

confidence: 99%

The Rac GTPase in Cancer: From Old Concepts to New Paradigms

2017

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Rho family GTPases are critical regulators of cellular functions that play important roles in cancer progression. Aberrant activity of Rho small G-proteins, particularly Rac1 and their regulators, is a hallmark of cancer, and contributes to the tumorigenic and metastatic phenotypes of cancer cells. This review examines the multiple mechanisms leading to Rac1 hyperactivation, particularly focusing on emerging paradigms that involve gain-of-function mutations in Rac and guanine nucleotide exchange factors (GEFs), defects in Rac1 degradation, and mislocalization of Rac signaling components. The unexpected pro-oncogenic functions of Rac GTPase activating proteins (GAPs) also challenged the dogma that these negative Rac regulators solely act as tumor suppressors. The potential contribution of Rac hyperactivation to resistance to anti-cancer agents, including targeted therapies, as well as to the suppression of anti-tumor immune response, highlights the critical need to develop therapeutic strategies to target the Rac pathway in a clinical setting.

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Pharmacological inhibition of Rac1-PAK1 axis restores tamoxifen sensitivity in human resistant breast cancer cells

Cited by 33 publications

References 48 publications

Computational and in vitro Pharmacodynamics Characterization of 1A-116 Rac1 Inhibitor: Relevance of Trp56 in Its Biological Activity

Computational and in vitro Pharmacodynamics Characterization of 1A-116 Rac1 Inhibitor: Relevance of Trp56 in Its Biological Activity

MiR‐142‐3p functions as a tumor suppressor by targeting RAC1/PAK1 pathway in breast cancer

The Rac GTPase in Cancer: From Old Concepts to New Paradigms

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