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Elucidating the molecular signaling pathways of WAVE3.

ABSTRACT: Cancer metastasis is a complex, multistep process that requires tumor cells to evade from the original site and form new tumors at a distant site or a different organ, often via bloodstream or the lymphatic system. Metastasis is responsible for more than 90% of cancer-related deaths. WAVE3 belongs to the Wiskott-Aldrich syndrome protein (WASP) family, which regulate actin cytoskeleton remodeling as well as several aspects of cell migration, invasion, and metastasis. In fact, WAVE3 has been established as a driver of tumor progression and metastasis in cancers from several origins, including triple negative breast cancers (TNBCs), which are classified as the most lethal subtype of breast cancer, due to their resistance to standard of care therapy and highly metastatic behavior. In this review, we will attempt to summarize the recent advances that have been made to understand how WAVE3 contributes to the molecular mechanisms that control cancer progression and metastasis. We will also review the signaling pathways that are involved in the regulation of WAVE3 expression and function to identify potential therapeutic options targeted against WAVE3 for the treatment of patients with metastatic tumors.

SUBMITTER: Kansakar U

PROVIDER: S-EPMC7396796 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Elucidating the molecular signaling pathways of WAVE3.

Kansakar Urna U Wang Wei W Markovic Vesna V Sossey-Alaoui Khalid K

Annals of translational medicine 20200701 14

Cancer metastasis is a complex, multistep process that requires tumor cells to evade from the original site and form new tumors at a distant site or a different organ, often via bloodstream or the lymphatic system. Metastasis is responsible for more than 90% of cancer-related deaths. WAVE3 belongs to the Wiskott-Aldrich syndrome protein (WASP) family, which regulate actin cytoskeleton remodeling as well as several aspects of cell migration, invasion, and metastasis. In fact, WAVE3 has been estab ...[more]

PMID: 32793744

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Project description:AimLoss of skeletal muscle mass is a common clinical finding in cancer patients. The purpose of this meta-analysis and systematic review was to quantify the effect of doxorubicin on skeletal muscle and report on the proposed molecular pathways possibly leading to doxorubicin-induced muscle atrophy in both human and animal models.MethodsA systematic search of the literature was conducted in PubMed, EMBASE, Web of Science and CENTRAL databases. The internal validity of included studies was assessed using SYRCLE's risk of bias tool.ResultsTwenty eligible articles were identified. No human studies were identified as being eligible for inclusion. Doxorubicin significantly reduced skeletal muscle weight (ie EDL, TA, gastrocnemius and soleus) by 14% (95% CI: 9.9; 19.3) and muscle fibre cross-sectional area by 17% (95% CI: 9.0; 26.0) when compared to vehicle controls. Parallel to negative changes in muscle mass, muscle strength was even more decreased in response to doxorubicin administration. This review suggests that mitochondrial dysfunction plays a central role in doxorubicin-induced skeletal muscle atrophy. The increased production of ROS plays a key role within this process. Furthermore, doxorubicin activated all major proteolytic systems (ie calpains, the ubiquitin-proteasome pathway and autophagy) in the skeletal muscle. Although each of these proteolytic pathways contributes to doxorubicin-induced muscle atrophy, the activation of the ubiquitin-proteasome pathway is hypothesized to play a key role. Finally, a limited number of studies found that doxorubicin decreases protein synthesis by a disruption in the insulin signalling pathway.ConclusionThe results of the meta-analysis show that doxorubicin induces skeletal muscle atrophy in preclinical models. This effect may be explained by various interacting molecular pathways. Results from preclinical studies provide a robust setting to investigate a possible dose-response, separate the effects of doxorubicin from tumour-induced atrophy and to examine underlying molecular pathways. More research is needed to confirm the proposed signalling pathways in humans, paving the way for potential therapeutic approaches.

Project description:BackgroundMetastatic breast cancer is responsible for the death of the majority of breast cancer patients. In fact, metastatic BC is the 2nd leading cause of cancer-related deaths in women in the USA and worldwide. Triple negative breast cancer (TNBC), which lacks expression of hormone receptors (ER-α and PR) and ErbB2/HER2, is especially lethal due to its highly metastatic behavior, propensity to recur rapidly, and for its resistance to standard of care therapies, through mechanisms that remain incompletely understood. WAVE3 has been established as a promoter of TNBC development and metastatic progression. In this study, we investigated the molecular mechanisms whereby WAVE3 promotes therapy-resistance and cancer stemness in TNBC, through the regulation of β-catenin stabilization.MethodsThe Cancer Genome Atlas dataset was used to assess the expression of WAVE3 and β-catenin in breast cancer tumors. Kaplan-Meier Plotter analysis was used to correlate expression of WAVE3 and β-catenin with breast cancer patients' survival probability. MTT assay was used to quantify cell survival. CRISPR/Cas9-mediated gene editing, 2D and 3D tumorsphere growth and invasion assays, Immunofluorescence, Western blotting, Semi-quantitative and real-time quantitative PCR analyses were applied to study the WAVE3/β-catenin oncogenic signaling in TNBC. Tumor xenograft assays were used to study the role of WAVE3 in mediating chemotherapy resistance of TNBC tumors.ResultsGenetic inactivation of WAVE3 in combination of chemotherapy resulted in inhibition of 2D growth and 3D tumorsphere formation and invasion of TNBC cells in vitro, as well as tumor growth and metastasis in vivo. In addition, while re-expression of phospho-active WAVE3 in the WAVE3-deficient TNBC cells restored the oncogenic activity of WAVE3, re-expression of phospho-mutant WAVE3 did not. Further studies revealed that dual blocking of WAVE3 expression or phosphorylation in combination with chemotherapy treatment inhibited the activity and expression and stabilization of β-catenin. Most importantly, the combination of WAVE3-deficiency or WAVE3-phospho-deficiency and chemotherapy suppressed the oncogenic behavior of chemoresistant TNBC cells, both in vitro and in vivo.ConclusionWe identified a novel WAVE3/β-catenin oncogenic signaling axis that modulates chemoresistance of TNBC. This study suggests that a targeted therapeutic strategy against WAVE3 could be effective for the treatment of chemoresistant TNBC tumors.

Project description:Stress and glucocorticoid hormones regulate hippocampal neurogenesis, but the molecular mechanisms underlying their effects are unknown. We, therefore, investigated the molecular signaling pathways mediating the effects of cortisol on proliferation, neuronal differentiation, and astrogliogenesis, in an immortalized human hippocampal progenitor cell line. In addition, we examined the molecular signaling pathways activated in the hippocampus of prenatally stressed rats, characterized by persistently elevated glucocorticoid levels in adulthood. In human hippocampal progenitor cells, we found that low concentrations of cortisol (100 nM) increased proliferation (+16%), decreased neurogenesis into microtubule-associated protein 2 (MAP2)-positive neurons (-24%) and doublecortin (Dcx)-positive neuroblasts (-21%), and increased differentiation into S100?-positive astrocytes (+23%). These effects were dependent on the mineralocorticoid receptor (MR) as they were abolished by the MR antagonist, spironolactone, and mimicked by the MR-agonist, aldosterone. In contrast, high concentrations of cortisol (100 ?M) decreased proliferation (-17%) and neuronal differentiation into MAP2-positive neurons (-22%) and into Dcx-positive neuroblasts (-27%), without regulating astrogliogenesis. These effects were dependent on the glucocorticoid receptor (GR), blocked by the GR antagonist RU486, and mimicked by the GR-agonist, dexamethasone. Gene expression microarray and pathway analysis showed that the low concentration of cortisol enhances Notch/Hes-signaling, the high concentration inhibits TGF?-SMAD2/3-signaling, and both concentrations inhibit Hedgehog signaling. Mechanistically, we show that reduced Hedgehog signaling indeed critically contributes to the cortisol-induced reduction in neuronal differentiation. Accordingly, TGF?-SMAD2/3 and Hedgehog signaling were also inhibited in the hippocampus of adult prenatally stressed rats with high glucocorticoid levels. In conclusion, our data demonstrate novel molecular signaling pathways that are regulated by glucocorticoids in vitro, in human hippocampal progenitor cells, and by stress in vivo, in the rat hippocampus.

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Elucidating the molecular signaling pathways of WAVE3.

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Elucidating the molecular signaling pathways of WAVE3.

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