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  • In this study using the


    In this study, using the RBD (Byr2)-GST pull-down assay associated with mass spectrometry, we also detected some kinases interacting with Ras-GTP under NO treatment. Among the kinases identified by mass spectrometry, we highlight Ste11 (designated Byr2 in S. pombe), Ste7 (Byr1) and Hog1. Interestingly, these kinases are part of a signaling pathway involved in the response to different stress types [33]. Hog1 is a component of a highly conserved MAP kinase pathway involved classically in osmo-adaptation in other yeasts [61,62]. In C. albicans, this MAP kinase (MAPK) is activated by the MAP kinase (MAPKK) Pbs2 (designated Ste7 in S. cerevisiae), which in turn is activated by a single MAP kinase kinase (MAPKKK), Ste11 [33,63,64]. In addition, the Hog1 pathway is also known as an important defense mechanism against oxidative stress [65,66]. Our data revealed the activation mechanism for Hog1 during NO-induced nitrosative stress in P. brasiliensis (Fig. 6). Recently, Herrero-de-Dios et al. [67] also showed that Hog1 MAPK contributes to nitrosative stress resistance in C. albicans. Mechanisms to detoxify RNS are broadly conserved, since they are found in organisms ranging from bacteria to humans [68]. Fungi consume NO primarily by a flavohaemoglobin, nitric oxide dioxygenase (Yhb1), which is present in the cytosol and mitochondrial matrix and indirectly participates in the oxidative stress [69]. As expected, the communication between signaling pathways, which respond to oxidative or nitrosative stress, seems to share some components [22]. MAPK are ubiquitous components in the response to almost any stresses imposed on Dynasore sale [21,70,71]. We observed that after Ras inhibition, some genes involved in oxidative (e.g., TRX, SOD, and GR) and nitrosative (YHB1) stress responses decreased their expression after treatment with high concentrations of NO. The response of C. albicans to oxidative stress is primarily mediated by Cap1 (AP-1 like) and Hog1 signaling [20,[72], [73], [74]], while the resistance to nitrosative stress is dependent on the transcription factor Cta4 [75]. In Sporothrix spp., it was also observed that the signaling pathway to oxidative stress is conserved and that Cap1 also participates in this response [76]. Thus, our data suggest that nitrosative stress activates cross-talk between the Ras-Hog1 pathway that probably mediates the activation of AP-1 and Cta4 transcription factors in P. brasiliensis (Fig. 6). Cross-talk between the Ras and Hog1 pathways has been confirmed in S. cerevisiae, C. albicans and Beauveria bassiana [[77], [78], [79], [80], [81], [82], [83]]. However, in these different studies, it was verified that the types of responses, activation or inhibition of Ras, varied according to the stimulus. Ras pathway signaling is a critical virulence determinant in pathogenic fungi [8,84], and therefore, this pathway has been explored as a potential target for novel antifungal therapies [84]. Finally, based on all this evidence, our findings provide the first insight into the significance of Ras-GTPase and Hog1 MAPK pathways for the P. brasiliensis adaptation to nitrosative stress.
    Introduction Cancer metastasis is the major cause of cancer mortality, accounting for approximately 90% of deaths. Once cancer cells leave and spread beyond their primary site, metastatic cancers are highly incurable and fatal, whereas most primary tumors are manageable or curable [1]. Prostate cancer is the most frequently diagnosed cancer in men with an estimated 180,000 new cases in U.S. in 2016. Five-year relative survival rate of localized and regional prostate cancer reaches approximately 99%; however, only about 27% of metastatic prostate cancer patients survive in 5 years [2]. Cancer metastasis is a complicated progress that involves four essential steps: detachment, migration, invasion and adhesion [3]. Whereas our understanding of the biology behind mechanisms of androgen receptor pathway activation, tumor-microenvironment interaction, and anti-tumor immunotherapy has advanced therapies for metastatic prostate cancer [4], a better understanding of molecular and cellular mechanisms of suppressor gene and associated signaling pathway in prostate cancer metastasis is critical and in great need to identify new therapeutic targets and agents.