ABSTRACT
Rac1 GTPase signaling pathway has a critical role in the regulation of a plethora of cellular functions governing cancer cell behavior. Recently, it has been shown a critical role of Rac1 in the emergence of resistance mechanisms to cancer therapy. This review describes the current knowledge regarding Rac1 pathway deregulation and its association with chemoresistance, radioresistance, resistance to targeted therapies and immune evasion. This supports the idea that interfering Rac1 signaling pathway could be an interesting approach to tackle cancer resistance.
Subject(s)
Drug Resistance, Neoplasm/genetics , Neoplasms/drug therapy , Neoplasms/radiotherapy , Radiation Tolerance/genetics , rac1 GTP-Binding Protein/physiology , Animals , Humans , Molecular Targeted Therapy , Neoplasms/genetics , Signal Transduction/genetics , Tumor Escape/geneticsABSTRACT
Tamoxifen is a standard endocrine therapy for estrogen receptor positive breast cancer patients. Despite its success, development of resistance mechanisms is still a serious clinical problem. Deregulation of survival signaling pathways play a key role in tamoxifen resistance, being upregulation of Rac1-PAK1 signaling pathway one of the most important. Here, we report the development of the breast cancer cell model MCF7::C1199 having Rac1 enhanced activity with the aim of evaluating the role of Rac1 in acquired endocrine resistance. These cells not only showed distinctive features of Rac1-regulated process as increased migration and proliferation rates, but also showed that upregulation of Rac1 activity triggered a hormonal-independent and tamoxifen resistant phenotype. We also demonstrated that PAK1 activity increases in response to Tamoxifen, increasing phosphorylation levels of estrogen receptor at Ser305, a key phosphorylation site involved in tamoxifen resistance. Finally, we evaluated the effect of 1A-116, a specific Rac1 inhibitor developed by our group, in tamoxifen-resistant cells. 1A-116 effectively restored tamoxifen anti-proliferative effects, switched off PAK1 activity and decreased estrogen receptor phospho-Ser305 levels. Since combination schemes of novel targeted agents with endocrine therapy could be potential new strategies to restore tamoxifen sensibility, these results show that inhibition of Rac1-PAK1 signaling pathway may provides benefits to revert resistance mechanisms in endocrine therapies.
Subject(s)
Breast Neoplasms/enzymology , Breast Neoplasms/pathology , Protein Kinase Inhibitors/pharmacology , Signal Transduction/drug effects , Tamoxifen/pharmacology , p21-Activated Kinases/antagonists & inhibitors , rac1 GTP-Binding Protein/antagonists & inhibitors , Drug Resistance, Neoplasm/drug effects , Estrogens/pharmacology , Female , Humans , MCF-7 Cells , Models, Biological , Phenotype , Phosphorylation/drug effects , Phosphoserine/metabolism , Up-Regulation/drug effects , p21-Activated Kinases/metabolism , rac1 GTP-Binding Protein/metabolismABSTRACT
We investigated the antitumor properties of a Solanum tuberosum extract (STE) on F3II mouse mammary carcinoma cells. STE significantly inhibited adhesion on fibronectin-coated surfaces and blocked migration of tumor cells in vitro. A major gelatinolytic activity (gelatinase) of 82 kD was identified in STE by zymographic analysis and characterized by exposure to different experimental conditions. Proteolytic activity of STE may be responsible, at least in part, for the in vitro effects on mammary carcinoma cells.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Phytotherapy , Plant Extracts/pharmacology , Solanum tuberosum/therapeutic use , Animals , Antineoplastic Agents, Phytogenic/therapeutic use , Gelatinases/metabolism , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/metabolism , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Inbred C3H , Neoplasm Invasiveness , Plant Extracts/therapeutic use , Tumor Cells, Cultured/drug effectsABSTRACT
We have examined the role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in tumor-bearing BALB/c mice using the syngeneic F3II mammary carcinoma. In the present model, progression of subcutaneous tumors induced massive myelopoiesis in bone marrow and spleen due to GM-CSF secretion by tumor cells. In vitro, the addition of recombinant mouse GM-CSF (5- 25 ng/ml) caused a significant increase in F3II cell growth, either in the presence or absence of serum. Zymographic analysis of conditioned media from F3II monolayers showed that GM-CSF exerted a dose-dependent enhancement in the metalloproteinases MMP-9 (105 kD) and MMP-2 (70 kD), key enzymes in mammary tumor cell invasion. Our data suggest that ectopic GM-CSF production stimulates myelopoiesis and may also play an important role in tumor progression and metastasis formation.
