Crosstalk Of Signaling Pathways Research Articles

Empowering crop resilience to environmental multiple stress through the modulation of key response components

Crop plants have developed a multitude of defense and adaptation responses to protect themselves against invading pathogens and challenging environmental stresses, mostly operating jointly. The plant perception of overall stress induces a coordinated response mediated by complex signaling networks. Experimental evidences proved that plant response to combined biotic and abiotic stresses substantially diverge from the responses to individual stresses. Moreover, the cross-talk of signaling pathways involved in responding to biotic and abiotic stresses is pivoted on several converging elements able to simultaneously modulate the timing and amplitude of the overall plant response. Comprehensively, the interaction between biotic and abiotic stresses can dramatically changes the plant response to the individual stress and the phenotypical outcome of each stress factor. System biology and data mining can synergistically help biologists in finding out regulative mechanisms and key genes controlling the response to biotic and abiotic stresses. Deploying new genetic engineering solutions can rely on the modification of genes involved in resistance/tolerance processes and/or in the modulation of regulatory elements. Finally, a model of the engineered crop for enhanced tolerance to pressures resulting from invasive pathogens and abiotic constraints in semiarid and warm environment is discussed.

Caveolin-1 Promotes Chemoresistance of Gastric Cancer Cells to Cisplatin by Activating WNT/β-Catenin Pathway

Drug resistance is a major challenge for chemotherapy in treating human gastric cancer (GC), as the underlying molecular mechanism of chemoresistance in GC remains unknown. Caveolin-1 (Cav-1) is a scaffold protein of plasma membrane caveolae that acts as a tumor modulator by interacting with several cell signals. In this research, we showed that the survival rate of GC cells to cisplatin (CDDP) increased in the presence of Cav-1. Moreover, Cav-1 overexpression inhibited cisplatin-induced apoptosis and improved the survival rate of GC cells. Cav-1 overexpression and knock-down experiments indicated that Cav-1 expression stimulated wingless-type MMTV integration site (WNTs) pathway through the phosphorylation of LRP6 and dephosphorylation of β-catenin. Cav-1 was positively associated with the increase of WNT downstream target gene Met, which led to the activation of HER2 signaling. Moreover, our results demonstrated that the expression of Cav-1 and Met were positively associated with the resistance of GC cells to cisplatin. Collectively, Cav-1 enhances the cisplatin-resistance of GC cells by activating the WNT signaling pathway and Met-HER2 crosstalk. Understanding the role of Cav-1 in the chemoresistance of GC would help to develop novel therapies for a better treatment outcome of GC patients.

Combined Analysis of the Aberrant Epigenetic Alteration of Pancreatic Ductal Adenocarcinoma.

Background Pancreatic ductal adenocarcinoma (PDAC) remains one of the most fatal malignancies due to its high morbidity and mortality. DNA methylation exerts a vital part in the development of PDAC. However, a mechanistic role of mutual interactions between DNA methylation and mRNA as epigenetic regulators on transcriptomic alterations and its correlation with clinical outcomes such as survival have remained largely uncovered in cancer. Therefore, elucidation of aberrant epigenetic alteration in the development of PDAC is an urgent problem to be solved. In this work, we conduct an integrative epigenetic analysis of PDAC to identify aberrant DNA methylation-driven cancer genes during the occurrence of cancer. Methods DNA methylation matrix and mRNA profile were obtained from the TCGA database. The integration of methylation and gene expression datasets was analyzed using an R package MethylMix. The genes with hypomethylation/hypermethylation were further validated in the Kaplan–Meier analysis. The correlation analysis of gene expression and aberrant DNA methylation was also conducted. We performed a pathway analysis on aberrant DNG methylation genes identified by MethylMix criteria using ConsensusPathDB. Results 188 patients with both methylation data and mRNA data were considered eligible. A mixture model was constructed, and differential methylation genes in normal and tumor groups using the Wilcoxon rank test was performed. With the inclusion criteria, 95 differential methylation genes were detected. Among these genes, 74 hypermethylation and 21 hypomethylation genes were found. The pathway analysis revealed an increase in hypermethylation of genes involved in ATP-sensitive potassium channels, Robo4, and VEGF signaling pathways crosstalk, and generic transcription pathway. Conclusion Integrated analysis of the aberrant epigenetic alteration in pancreatic ductal adenocarcinoma indicated that differentially methylated genes could play a vital role in the occurrence of PDAC by bioinformatics analysis. The present work can help clinicians to elaborate on the function of differentially methylated expressed genes and pathways in PDAC. CDO1, GJD2, ID4, NOL4, PAX6, TRIM58, and ZNF382 might act as aberrantly DNA-methylated biomarkers for early screening and therapy of PDAC in the future.

Understanding the crosstalk of molecular factors and signaling pathways reveals novel biomarkers of cisplatin resistance in testicular germ cell tumors.

Testicular germ cell tumors (TGCTs) mostly affect young men, but fortunately belong to well curable solid tumors. Today, different treatment strategies are applied reaching excellent outcomes, and introduction of alternative approach of patient active surveillance or adjuvant chemotherapy after orchiectomy decreases number of unnecessary toxic treatments of young patients. Also for relapsing patients, salvage therapy offers high survival rates. However, small percentages of affected young men do not respond to conventional therapy regimen due to intrinsic or acquired therapy resistance. For closely watching of patients during active surveillance, patients' stratification due to their prognosis, detection of therapy resistance and early relapse before treatment initiation, reliable molecular biomarkers and diagnostic tools replacing conventional approaches are still needed. Complex understanding of disease development and progression as well as mechanisms of chemoresistance and their epigenetic or chronobiological regulation pre-requisite successful search for such novel biomarkers. In this review, we aimed to highlight the importance of crosstalk of different regulatory mechanisms and their key players affecting treatment response, and focus on their potential as novel molecular biomarkers and/or druggable targets.

Hypoxia regulates the mitochondrial activity of hepatocellular carcinoma cells through HIF/HEY1/PINK1 pathway

Hypoxia is commonly found in cancers. Hypoxia, due to the lack of oxygen (O2) as the electron recipient, causes inefficient electron transfer through the electron transport chain at the mitochondria leading to accumulation of reactive oxygen species (ROS) which could create irreversible cellular damages. Through hypoxia-inducible factor 1 (HIF-1) which elicits various molecular events, cells are able to overcome low O2. Knowledge about the new molecular mechanisms governed by HIF-1 is important for new therapeutic interventions targeting hypoxic tumors. Using hepatocellular carcinoma (HCC) as a model, we revealed that the HIF-1 and the Notch signaling pathways cross-talk to control mitochondrial biogenesis of cancer cells to maintain REDOX balance. From transcriptome sequencing, we found that HEY1, a transcriptional repressor, in the NOTCH pathway was consistently induced by hypoxia in HCC cell lines. We identified a strong hypoxia response element (HRE) in HEY1 by chromatin immunoprecipitation (ChIP) and luciferase reporter assays. Transcriptome and ChIP sequencing further identified PINK1, a gene essential for mitochondrial biogenesis, as a novel transcriptional target of HEY1. HCC cells with HEY1 knockdown re-expressed PINK1. HEY1 and PINK1 expressions inversely correlated in human HCC samples. Overexpression of HEY1 and under-expression of PINK1 were detected in human HCC and associated with poor clinical outcomes. Functionally, we found that overexpression of HEY1 or knockdown of PINK1 consistently reduced mitochondrial cristae, mitochondrial mass, oxidative stress level, and increased HCC growth.

Comprehensive In Vitro Testing of Calcium Phosphate-Based Bioceramics with Orthopedic and Dentistry Applications.

Recently, a large spectrum of biomaterials emerged, with emphasis on various pure, blended, or doped calcium phosphates (CaPs). Although basic cytocompatibility testing protocols are referred by International Organization for Standardization (ISO) 10993 (parts 1–22), rigorous in vitro testing using cutting-edge technologies should be carried out in order to fully understand the behavior of various biomaterials (whether in bulk or low-dimensional object form) and to better gauge their outcome when implanted. In this review, current molecular techniques are assessed for the in-depth characterization of angiogenic potential, osteogenic capability, and the modulation of oxidative stress and inflammation properties of CaPs and their cation- and/or anion-substituted derivatives. Using such techniques, mechanisms of action of these compounds can be deciphered, highlighting the signaling pathway activation, cross-talk, and modulation by microRNA expression, which in turn can safely pave the road toward a better filtering of the truly functional, application-ready innovative therapeutic bioceramic-based solutions.

Crosstalk of BMP-4 and RA signaling pathways on Pomc gene regulation in corticotrophs.

Retinoic acid (RA), an active metabolite of Vitamin A, and bone morphogenetic protein 4 (BMP-4) pathways control the transcription of pro-opiomelanocortin (Pomc), the precursor of ACTH. We describe a novel mechanism by which RA and BMP-4 act together in the context of pituitary corticotroph tumoral cells to regulate Pomc transcription. BMP-4 and RA exert a potentiated inhibition on Pomc gene expression. This potentiation of the inhibitory action on Pomc transcription was blocked by the inhibitory SMADs of the BMP-4 pathway (SMAD6 and SMAD7), a negative regulator of BMP-4 signaling (TOB1) and a blocker of RA pathway (COUP-TFI). AtT-20 corticotrophinoma cells express RA receptors (RARB, RXRA and RXRG) which associate with factors of BMP-4 (SMAD4 and SMAD1) signaling cascade in transcriptional complexes that block Pomc transcription. COUP-TFI and TOB1 disrupt these complexes. Deletions and mutations of the Pomc promoter and a specific DNA-binding assay show that the complexes bind to the RARE site in the Pomc promoter. The enhanced inhibitory interaction between RA and BMP-4 pathways occurs also in another relevant corticotroph gene promoter, the corticotropin-releasing hormone receptor 1 (Crh-r1). The understanding of the molecules that participate in the control of corticotroph gene expression contribute to define more precise targets for the treatment of corticotrophinomas.

The Calmodulin-Binding Protein IQM1 Interacts with CATALASE2 to Affect Pathogen Defense.

Calmodulin (CaM) regulates plant disease responses through its downstream calmodulin-binding proteins (CaMBPs) often by affecting the biosynthesis or signaling of phytohormones, such as jasmonic acid (JA) and salicylic acid. However, how these CaMBPs mediate plant hormones and other stress resistance-related signaling remains largely unknown. In this study, we conducted analyses in Arabidopsis (Arabidopsis thaliana) on the functions of AtIQM1 (IQ-Motif Containing Protein1), a Ca2+-independent CaMBP, in JA biosynthesis and defense against the necrotrophic pathogen Botrytis cinerea using molecular, biochemical, and genetic analyses. IQM1 directly interacted with and promoted CATALASE2 (CAT2) expression and CAT2 enzyme activity and indirectly increased the activity of the JA biosynthetic enzymes ACX2 and ACX3 through CAT2, thereby positively regulating JA content and B. cinerea resistance. In addition, in vitro assays showed that in the presence of CaM5, IQM1 further enhanced the activity of CAT2, suggesting that CaM5 may affect the activity of CAT2 by combining with IQM1 in the absence of Ca2+ Our data indicate that IQM1 is a key regulatory factor in signaling of plant disease responses mediated by JA. The study also provides new insights that CaMBP may play a critical role in the cross talk of multiple signaling pathways in the context of plant defense processes.

Sucrose and methyl jasmonate modulate the expression of anthocyanin biosynthesis genes and increase the frequency of flower-color mutants in chrysanthemum

γ-rays have been used to develop many mutations in diverse ornamental plants, including chrysanthemum, of which most changes have been flower color. Flower color is determined by plant pigments, including anthocyanins, which are affected by mutation of genes in the anthocyanin biosynthesis pathway. Sucrose and plant hormones also crosstalk in complex signaling pathways and modulate anthocyanin biosynthesis. In this study, we determined the optimal sucrose and plant hormone treatments for expression of anthocyanin biosynthesis genes and compared the mutation frequency among sucrose, methyl jasmonate (MeJA), and/or γ-ray treatments in chrysanthemum. Anthocyanin biosynthesis genes were highly expressed with 50 mM sucrose treatment for 18 h. The highest expression levels of anthocyanin biosynthesis genes were observed under sucrose with MeJA treatment followed by MeJA treatment alone. Sucrose with abscisic acid (ABA) treatment, and ABA or GA3 treatment alone, had no effect on expression of anthocyanin biosynthesis genes. Sucrose with MeJA pre-treatment followed by γ-irradiation resulted in the highest mutation frequency (14.5%) among all treatments and a 1.5-fold increase in mutation frequency compared with γ-ray treatment alone. The ratio of anthocyanin-related flower-color mutants with sucrose and/or MeJA pre-treatments followed by γ-irradiation was higher than that with γ-ray treatment alone. Sucrose and/or MeJA modulated the expression of anthocyanin biosynthesis genes and highly expressed genes may be affected more readily by γ-rays, thus resulting in an increased frequency of anthocyanin-related flower-color mutants in chrysanthemum.

Crosstalk of Intercellular Signaling Pathways in the Generation of Midbrain Dopaminergic Neurons In Vivo and from Stem Cells.

Dopamine-synthesizing neurons located in the mammalian ventral midbrain are at the center stage of biomedical research due to their involvement in severe human neuropsychiatric and neurodegenerative disorders, most prominently Parkinson’s Disease (PD). The induction of midbrain dopaminergic (mDA) neurons depends on two important signaling centers of the mammalian embryo: the ventral midline or floor plate (FP) of the neural tube, and the isthmic organizer (IsO) at the mid-/hindbrain boundary (MHB). Cells located within and close to the FP secrete sonic hedgehog (SHH), and members of the wingless-type MMTV integration site family (WNT1/5A), as well as bone morphogenetic protein (BMP) family. The IsO cells secrete WNT1 and the fibroblast growth factor 8 (FGF8). Accordingly, the FGF8, SHH, WNT, and BMP signaling pathways play crucial roles during the development of the mDA neurons in the mammalian embryo. Moreover, these morphogens are essential for the generation of stem cell-derived mDA neurons, which are critical for the modeling, drug screening, and cell replacement therapy of PD. This review summarizes our current knowledge about the functions and crosstalk of these signaling pathways in mammalian mDA neuron development in vivo and their applications in stem cell-based paradigms for the efficient derivation of these neurons in vitro.

PlGF knockdown induced apoptosis through Wnt signaling pathway in gastric cancer stem cells.

Despite the fact that much research has focused on gastric cancer, it is still a worldwide concern, because of the difficulties with factors such as signaling pathway crosstalk and gastric cancer stem cell (GCSC). Placental growth factor (PlGF) is one of these factors, and its tumorigenicity potential still remains a question. As a result, we have investigated the effect of PlGF knockdown on apoptosis and genes involved in the Wnt signaling pathway, and apoptosis in cancer stem cells derived from AGS an MKN-45 gastric cancer cell lines. We isolated GCSCs from MKN-45 and AGS cell lines on a nonadherent surface. Then the cell viability, the real-time reverse transcription-polymerase chain reaction data of the genes involved in the Wnt signaling pathway, and apoptosis were evaluated. Furthermore, DNA laddering was used to show the apoptotic effect and DNA fragmentation caused by the PlGF knockdown. Our investigation revealed that the PlGF knockdown with PlGF-specific small interfering RNA at 40 pmol for GCSCs derived from MKN-45 and AGS at 24 hours can significantly affect the cell viability, the Wnt signaling pathway, and the apoptosis-related genes expression. In conclusion, we showed the PlGF knockdown may induce apoptosis via the Wnt signaling pathway in GCSCs.

Abstract B35: Palbociclib treatment activates FAK and use of palbociclib in combination with the FAK inhibitor PF-562,271 enhances antitumor activity in ER-positive breast cancer cells

Abstract Cell survival and proliferation is tightly regulated by a number of interacting coordinated signaling proteins including the cyclin-dependent kinases (CDK). Palbociclib, a CDK4/6 inhibitor, has recently been shown to be very effective in the treatment of estrogen receptor (ER) positive breast cancer; however, many patients develop an acquired resistance through as yet incompletely characterized mechanisms. One recently proposed mechanism is compensation by CDK2 (Herrera-Abreu et al., Can Res 2016;76:2301). Focal adhesion kinase (FAK) is a tyrosine kinase that plays a central role in signaling pathway crosstalk and cell survival and invasion. FAK has been previously shown to activate CDK2 in hepatocytes (Flinder et al., J Cell Phys 2013;228:1304), and given its important role in mediating cell survival, we were interested in determining whether FAK-mediated upregulation of CDK2 occurs in palbociclib-treated breast cancer cells, thereby limiting its efficacy. ER-positive MCF7, MDA-MB-134VI, and T47D breast cancer cell lines were thus treated with increasing doses of palbociclib. We observed dose-dependent increases in phospho-FAK Y397, a marker of the active kinase, following palbociclib treatment. We thus used PF-562,271, a selective FAK tyrosine kinase inhibitor, in combination with palbociclib and, not surprisingly, observed an enhanced ability to inhibit cell viability as compared to use of either drug alone. This was concomitant with observed increases in the CDK4/6 inhibitor p27, and with decreases in phospho-RB, which are indicative of reduced CDK2 activity, following treatment with PF-562,271. Our results highlight an unexpected side effect of palbociclib treatment, namely FAK activation, which could potentially contribute to resistance due to activation of CDK2 and inhibition of p27. The mechanism by which palbociclib activates FAK is currently under investigation. Citation Format: Grant Howe, Victoria Allen, Christina L. Addison. Palbociclib treatment activates FAK and use of palbociclib in combination with the FAK inhibitor PF-562,271 enhances antitumor activity in ER-positive breast cancer cells [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B35.

Xbra and Smad-1 cooperate to activate the transcription of neural repressor ventx1.1 in Xenopus embryos

Crosstalk of signaling pathways play crucial roles in cell proliferation, cell differentiation, and cell fate determination for development. In the case of ventx1.1 in Xenopus embryos, both BMP-4/Smad-1 and FGF/Xbra signaling induce the expression of neural repressor ventx1.1. However, the details of how these two pathways interact and lead to neural inhibition by ventx1.1 remain largely unknown. In the present study, Xbra directly bound to the ventx1.1 promoter region and inhibited neurogenesis in a Ventx1.1-dependent manner. Furthermore, Smad-1 and Xbra physically interacted and regulated ventx1.1 transcription in a synergistic fashion. Xbra and Smad-1 interaction cooperatively enhanced the binding of an interacting partner within the ventx1.1 promoter and maximum cooperation was achieved in presence of intact DNA binding sites for both Smad-1 and Xbra. Collectively, BMP-4/Smad-1 and FGF/Xbra signal crosstalk cooperate to activate the transcription of neural repressor ventx1.1 in Xenopus embryos. This suggests that the crosstalk between BMP-4 and FGF signaling negatively regulates early neurogenesis by synergistic activation of ventx1.1 in Xenopus embryos.

Selective Actionable and Druggable Protein Kinases Drive the Progression of Neuroendocrine Prostate Cancer.

Current clinical anti-androgen therapies in advanced prostate cancer (PCa) are driving an increased incidence of neuroendocrine prostate cancer (NEPC), a histological variant exhibiting reduced androgen receptor levels and expression of neuroendocrine markers. The mechanisms underlying the development of NEPC are poorly understood. A set of available data from a well-validated xenograft model of NEPC was used to analyze the exact role of protein kinase (PK) played in the development of NEPC. Fifty-four actionable and druggable PKs, mainly enriched in PI3K-Akt, mTOR, and MAPK signaling pathways, were screened out from the drastically changed PKs during NEPC transdifferentiation. Further analysis based on the crosstalk of these above signaling pathways finally singled out 10 PKs considered drivers and therapeutic targets in the development and treatment of NEPC. In vitro, the variation trend of PK expression observed during NEPC transdifferentiation could be recapitulated in PCa cell lines with different malignant degree. The predicted kinase targets exhibited different sensibilities in the restriction of PC3 cell growth. Selective actionable and druggable PKs may act as drivers in the progression of NEPC, and most of them can be used as potential therapeutic targets in clinical practice.

Abstract 943: SAR439859, an orally bioavailable selective estrogen receptor degrader (SERD) that demonstrates robust antitumor efficacy and limited cross-resistance in ER+ breast cancer

Abstract Despite resistance to endocrine therapies, estrogen receptor-positive (ER+) breast cancers (BC) still rely on ER. Eliminating ER by inducing its degradation with selective ER downregulators (SERD) should induce complete ablation of ER pathways. The clinical SERD fulvestrant, although it has demonstrated clinical benefits, is hampered by its poor drug properties and undesirable pharmacokinetics, undermining its optimal clinical activity. Therefore there is an unmet need for an improved therapy targeting ER. Here we describe SAR439859, a novel, nonsteroidal, orally bioavailable SERD currently in clinical trials. SAR439859 has a potent ER antagonist and ER degrading activity that translates in a robust inhibition of ER signaling in multiple ER+ breast cancer cell lines, including tamoxifen-resistant lines as well as cell lines harboring ER mutations. SAR439859 displays a broad and superior ER degradation activity across a large panel of ER+ cells. Importantly, based on its mechanism of action SAR439859 shows limited cross-resistance with other clinical SERD molecules. SAR439859 induces strong in vivo antitumor activity against a variety of BC cell lines and patient-derived xenografts, including models that harbor ERα mutations. The transcriptional profile analysis highlighted a crosstalk of ER mutant signaling and other oncogenic pathways. Interestingly, CDK4/6 inhibition by palbociclib induces partial activation of ER pathways as potential mechanism of tumor escape, which is completely abolished by the combination of SAR439859 with palbociclib. Finally, we demonstrate that SAR439859 in combination with palbociclib can lead to higher in vivo efficacy. This study highlights novel mechanism of ER degradation by SAR439859 that leads to profound inhibition of ER signaling as well as modulation of other oncogenic pathways and provides rationale for the ongoing clinical investigation of SAR439859 in ER+ breast cancer patients, both as a single agent and in combination with approved agents, such as CDK4 inhibitor. Citation Format: Monsif Bouaboula, Maysoun Shomali, Jane Cheng, Natalia Malkova, Fangxian Sun, Malvika Koundinya, Zhuyan Guo, Stephane Poirier, Mikhail Levit, Dietmar Hoffman, Hui Cao, Laurent Bestret, Francisco Adrian, Christoph Winter, Youssef El-Ahmad, Sylvie Vincent, Frank Halley, Gary McCort, Laurent Schio, Vicky Richon, Hong Cheng, Karl Hsu, Chris Soria, Patrick Cohen, Joanne Lager, Carlos Garcia-Echeverria, Laurent Debussche. SAR439859, an orally bioavailable selective estrogen receptor degrader (SERD) that demonstrates robust antitumor efficacy and limited cross-resistance in ER+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 943.

Ginseng Compatibility Environment Attenuates Toxicity and Keeps Efficacy in Cor Pulmonale Treated by Fuzi Beimu Incompatibility Through the Coordinated Crosstalk of PKA and Epac Signaling Pathways.

Cor pulmonale is characterized by severe right ventricular dysfunction caused by lung disease, particularly chronic obstructive pulmonary disease, which can lead to pulmonary hypertension. Our previous study has demonstrated that Fuzi and Beimu compatibility (FBC), a traditional TCM compatibility taboo, improves lung function in early-stage of pulmonary hypertension through the synergistic action of β-ARs signals. However, FBC increases cardiotoxicity with prolonged treatment and disease progression. Considering that the compatibility environment influences the exertion of the medicine, we selected ginseng for coordinating the compatibility environment to improve the security and extend the therapeutic time window of FBC. Monocrotaline-induced cor pulmonale rats were treated with FBC, ginseng, or ginseng combined with FBC (G/FBC). Then, the pulmonary and cardiac functions of the rats were examined to evaluate the toxicity and efficacy of the treatments. The crosstalk between PKA and Epac pathways was also studied. Results showed that G/FBC ameliorated lung function similar to or even better than FBC treatment did. Furthermore, G/FBC treatment attenuated FBC-induced cardiotoxicity, which significantly restored cardiac dysfunction and clearly decreased myocardial enzymes and apoptosis. The βAR-Gs-PKA/CaMKII pathway was inhibited and the Epac1/ERK1/2 axis was activated in G/FBC group. These findings indicate that ginseng compatibility environment could improve pulmonary function and attenuate cardiotoxicity in cor pulmonale via the coordinated crosstalk of PKA and Epac pathways, implying that ginseng could be used to prevent detrimental cardiotoxicity in cor pulmonale treatment.

Crosstalk of abnormal signaling pathways in human pituitary adenomas and the medication prospect

Pituitary adenomas, originating from adenohypophysis, are generally benign intracranial tumor. Multiple characteristics are identified in pituitary adenomas, including excess hormone secretion and cell proliferation. It is well established that excess hormone secretion and tumor cell proliferation are regulated by multiple signaling pathways in pituitary adenomas, which interact through crosstalk mechanisms and form a complex signaling network. This study aims to review the crosstalk in this signaling network and to elucidate the functional roles of key factors in regulating excess hormone secretion and tumor cell proliferation of pituitary adenomas. Targeting these key factors may provide new promising pharmacotherapy applications in the future. Key words: Pituitary adenomas; Signaling pathway; Pharmacotherapy

852 Short-term ozone exposure stimulates both IGF1R and EGFR to promote diabetic wound healing

Ozonated oil, containing the potent disinfectant and oxygen donor ozone (O3), improves wound oxygenation and closure after topical application. However, the mechanism of O3 action on skin cells during wound healing is largely unknown. We hypothesized that IGF1R/EGFR crosstalk and activation of downstream signaling pathways are required for the observed acceleration in wound healing. In a diet-induced obese diabetic mouse model, topical application of O3 oil visibly promoted healing with a 2-3-fold reduction in the epidermal gap and 1.7-fold increase in granulation tissue compared with vehicle-treated mice at 8 days after initiation (when wounds in nondiabetic mice had closed). Immunohistochemical staining showed a 2-2.5 fold increase in BrdU labeling index (p<.01) and a 1.9-2.3 fold increase in keratinocyte (KC) migration (p<.05) at the wound edge at 4-8 days post wounding. Brief exposure of monolayer cultured normal KCs to O3 (20 uM, 2 h) daily increased cell proliferation in high glucose (HG; p<.001) within 24h and normal glucose (NG: p<.01 NG vs. HG+O3) by 72h in WST assays. Exposure to O3 also enhanced cell migration (p<.001, HG vs. HG+O3 by 24h and p<.05 NG vs. NG+O3 by 60h in mouse KCs and p<.01 HG vs. HG+O3 by 6h and p<.05 NG vs. NG+O3 by 18h in human KCs) in scratch assays. Under NG condition, brief O3 exposure increased EGF-stimulated p-ERK by 1.7-fold, p-AKT at Thr 308 and p-PI3K by 2.1-fold and p-AKT at Ser 473 by 2.9-fold, and increased IGF-1 stimulated p-ERK by 1.5-fold. Interestingly, stimulation with EGF or IGF-1 reversed HG-induced inhibition on PI3K/Akt and ERK activation in the presence of O3, suggesting that brief O3 exposure ameliorate skin cell function under HG condition. The increase in KC proliferation and migration caused by O3 exposure was completely inhibited by disrupting EGFR and IGF1R simultaneously. These findings suggest that topical exposure to O3 requires activation of both EGFR and IGF1R to accelerate wound healing.

Molecular signatures in hepatocellular carcinoma: A step toward rationally designed cancer therapy

Molecular characterization of hepatocellular carcinoma (HCC) has greatly improved our understanding of disease pathogenesis. Mutational analysis, RNA and microRNA expression profiling, and epigenetic characterization have revealed common aberrations in oncogenes and tumor suppressors that correlate with disease biology and serve as a guide for the rational design of targeted therapies. These approaches have also led to the discovery of novel targets, including mutations in isocitrate dehydrogenase and chromatin remodeling enzymes. With the advent of immunotherapy, RNA expression profiling of the tumor microenvironment has identified a subset of HCC with high lymphocyte infiltration that may benefit from checkpoint inhibitor therapy. Molecular signatures thus capture the biology of a tumor, providing a supplement to current staging schema, which are based on tumor size and number, for more accurate prognostication of recurrence risk and survival. Molecular signatures may also be used to guide interventional therapy by defining those most suitable for transplantation or locoregional therapy rather than surgical resection. Finally, a multiomics approach involves the aggregation and analysis of multiple signatures for a more comprehensive characterization of pathogenic mechanisms. This broader approach attempts to address issues with signaling pathway cross-talk and redundancy, which have greatly limited the potential value of targeted therapies to date. Cancer 2018. © 2018 American Cancer Society.

Cross-talk between EGFR and IL-6 drives oncogenic signaling and offers therapeutic opportunities in cancer

Epidermal growth factor receptor (EGFR) is a known target in cancer therapy and targeting the receptor has proven to be extremely successful in treating cancers that are dependent on EGFR signaling. To that effect, targeted therapies to EGFR such as Cetuximab, Panitumumab-monoclonal antibodies and Gefitinib, Erlotinib-tyrosine kinase inhibitors have had success in therapeutic scenarios. However, the development of resistance to these drugs makes it necessary to combine anti- EGFR therapies with other inhibitors, so that resistance can be overcome by the targeting of alternate signaling pathways. On the other hand, components of the inflammatory pathway, within and around a tumor, provide a conducive environment for tumor growth by supplying numerous cytokines and chemokines that foster carcinogenesis. Interleukin 6 (IL-6) is one such cytokine that is found to be associated with inflammation-driven cancers and which also plays a crucial role in acquired resistance to anti-EGFR drugs. The EGFR and IL-6 signaling pathways crosstalk in multiple ways, through various mediators and downstream signaling pathways driving resistance and hence co-targeting them has potential for future cancer treatments. Here we provide an overview on the crosstalk between the EGFR and IL-6 pathways, and discuss how co-targeting these two pathways could be a promising combination therapy of the future.