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Monoclonal Antibodies in the Treatment of Malignant Lymphomas and Chronic Lymphocytic Leukemia
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Finally, evidences that rituximab could synergize with chemotherapeutic agents in B-cell killing were provided by Demidem (17). Subsequent investigations have confirmed synergy of rituximab with fludarabine, doxorubicin, and other anticancer drugs (18–20). In one hypothesis, this synergism is mediated, at least in part, via downregulation of interleukin-10 (IL-10) by rituximab, which in turn causes downregulation of the antiapoptotic protein bcl2 and increased sensitivity to apoptosis (21). Another mechanism involves the inhibition of the activity of P-glycoprotein and, thus, the efflux of drugs like doxorubicin or vincristine (22). In cell lines, the P-glycoprotein pump is translocated out of the lipids rafts. Studies performed with cell lines as model systems revealed several mechanisms that are involved in chemo/immunosensitization and the development of resistance to rituximab. Rituximab has been shown to inhibit the p38 mitogen-activated protein kinase, nuclear factor-κB (NF-κB), extracellular signal-regulated kinase 1/2 (ERK 1/2) and AKT antiapoptotic survival pathways, all of which result in upregulation of PTEN and Raf kinase inhibitor protein and in the downregulation of antiapoptotic gene products (particularly Bcl-2, Bcl-xL, and Mcl-1), and resulting in chemo/immunosensitization. Further, rituximab treatment inhibits the overexpressed transcription repressor Yin Yangl (YY1), which negatively regulates Fas and DR5 expression, and its inhibition leads to sensitization to Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis (23).
REGULATORY MECHANISMS
Published in David M. Gibson, Robert A. Harris, Metabolic Regulation in Mammals, 2001
David M. Gibson, Robert A. Harris
Another layer of control is seen in protein kinase inhibitors, such as RKIP (Raf Kinase Inhibitor Protein) which blocks the phosphorylation of Mek (MAPKK) bv the Raf I kinase (MAPKKK) in the Rail Mek MAPK(Hrk) module shown in Figure 3.8. An unrelated (lethal) "inhibitor" of the МАРК pathway is a 3 3kl)a protein, YopJ, which is injected into human cells bv the bacterium (Yersinia penis) that causes bubonic-plague.
NeiyiKangfu tablets control the progression of endometriosis through inhibiting RAF/MEK/ERK signal pathway by targeting RKIP
Published in Gynecological Endocrinology, 2022
Yi Wen, Lingxiu Fan, Lili Pang, Tingting Zhao, Ruonan Li, Ying Zhang, Liye Zhang, Wei Yang
Studies have reported that theories on the etiology of EMS include retrograde menstruation, celomic metaplasia, altered immunity, stem cells, and genetics, which affect gametes and embryos, fallopian tube and embryo transport, and ectopic endometrium. In addition, numerous studies have shown that RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling cascade is one of the key mitogen-activated protein kinase (MAPK) signal cascades for mediating the intracellular transmission of extracellular signals and inducing cellular processes [8]. RAS binds to RAF and then activates the downstream signal MEK1/2, followed by activation of ERK phosphorylation [8]. It has been reported that RAF/MEK/ERK plays an important regulatory role in cell growth, proliferation, migration, and apoptosis in many diseases [9], including endometrial cancer [10]. Moreover, activated RAF/MEK/ERK in the ectopic endometrium was observed [11], and was associated with the proliferation and migration of endometrial stromal cells in EMS [12]. Current evidence substantiates that RAF kinase inhibitor protein (RKIP) can combine with the RAF and interfere with the downstream RAF/MEK/ERK pathway, acting as a physiological endogenous inhibitor of the MAPK pathway [13]. However, the regulation of RAF/MEK/ERK signal in EMS is incompletely understood.
Antimetastatic Properties of Tea Polyphenols
Published in Nutrition and Cancer, 2020
Binding of hepatocyte growth factor (HGF) with its receptor Met causes autophosphorylation of the receptor. This results in activation of downstream signaling pathways, including AKT, Ras/MAPK, and the JAK/STAT pathways those are associated with increased cell motility, invasive properties (47). Bigelow and Cardelli (47) assessed the ability of EGCG to inhibit HGF signaling in an invasive breast carcinoma cell line MDA-MB-231. While HGF treatment induced rapid, sustained activation of Met, ERK, and AKT, pretreatment of cells with EGCG inhibited HGF-induced Met phosphorylation, activation of downstream signaling molecules, and cell motility. Other GTPs, e.g., ECG, EGC had antimotility effects although EC was unable to inhibit HGF-induced events. Kim and Kim demonstrated that EGCG could inhibit invasive metastasis in the AsPC-1 human pancreatic adenocarcinoma cell line by inducing the expression of Raf kinase inhibitor protein (RKIP) that inhibits Raf/MEK/ERK pathway (48). Studies also reported inhibitory effects of EGCG on invasiveness of multiple glioma cell lines (49).
Prognostic significance of proteomics and multi-omics studies in renal carcinoma
Published in Expert Review of Proteomics, 2020
Francesca Raimondo, Marina Pitto
Regarding phosphoproteomics, the already cited investigation performed on six different cancer types highlighted the peculiar phosphorylation pattern of RCC, compared to the other malignancies [23]. A few other papers analyzed specific pathways through different approaches. A proteomics SELDI-based analysis of 93 urinary samples of patients affected by RCC, compared with healthy subjects and other urological conditions, provided signatures specific for each condition. In particular, urinary excretion of Raf Kinase Inhibitor Protein – a key regulator of cell signaling – and its phosphorylated form was shown to be predictive for cancer-specific survival and progression-free survival in RCC [61]. van der Mijn et al. [62] evaluated global tyrosine phosphorylation by LC-MS/MS after immunoprecipitation with an anti-phosphotyrosine antibody in RCC 786-O cells treated or not with sunitinib. One hundred and eighty phospho-peptides resulted to be differentially regulated, among which tyrosine-protein kinase receptor UFO (AXL), a cell surface receptor tyrosine kinase, exhibited a significant upregulation. Its inhibition was shown to improve the antitumor activity of sunitinib [62]. A quantitative phosphoproteomic approach was applied to identify pyruvate kinase M2 (PKM2) substrates in RCC cells: the results underlined the importance of two phosphorylation sites on mTORC1 inhibitor AKT1 substrate 1, whose activation leads to accelerated oncogenic growth and autophagy inhibition in cancer cells. The deepening of PKM2 phosphorylome revealed a constitutive mTORC1 activating mechanism in RCC cells [63]. In a comparative study on RCC tissue and ANK, the authors investigated the role of Golgi phosphoprotein 3 (GOLPH3), a proto-oncogene product. Its expression was found to promote the proliferative and invasive capacity of RCC cells via phosphorylation of FAK/Raf1/MEK and further activation of Wnt/β-catenin signaling pathways, using a high-throughput phospho-proteome array verified by immunoblotting [64].