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Battle Vestergaard posted an update 6 months, 1 week ago
Protein tyrosine kinase 6 (PTK6) is the most well studied member of the PTK6 family of intracellular tyrosine kinases. While it is expressed at highest levels in differentiated cells in the regenerating epithelial linings of the gastrointestinal tract and skin, induction and activation of PTK6 is detected in several cancers, including breast and prostate cancer where high PTK6 expression correlates with worse outcome. PTK6 expression is regulated by hypoxia and cell stress, and its kinase activity is induced by several growth factor receptors implicated in cancer including members of the ERBB family, IGFR1 and MET. Activation of PTK6 at the plasma membrane has been associated with the epithelial mesenchymal transition and tumor metastasis. Several lines of evidence indicate that PTK6 has context dependent functions that depend on cell type, intracellular localization and kinase activation. Systemic disruption of PTK6 has been shown to reduce tumorigenesis in mouse models of breast and prostate cancer, and more recently small molecule inhibitors of PTK6 have exhibited efficacy in inhibiting tumor growth in animal models. Here we review data that suggest targeting PTK6 may have beneficial therapeutic outcomes in some cancers.Cancer cells take advantage of signaling cascades to meet their requirements for sustained growth and survival. Cell signaling is tightly controlled by reversible protein phosphorylation mechanisms, which require the counterbalanced action of protein kinases and protein phosphatases. Imbalances on this system are associated with cancer development and progression. Protein phosphatase 1 (PP1) is one of the most relevant protein phosphatases in eukaryotic cells. Despite the widely recognized involvement of PP1 in key biological processes, both in health and disease, its relevance in cancer has been largely neglected. Here, we provide compelling evidence that support major roles for PP1 in tumorigenesis.Exosomes, which facilitate intercellular communication, antigen presentation and shuttling of biological agents, were initially thought as the cell’s garbage cargo but today, after about 40 years of their discovery, we are now beginning to understand their potential role in diagnosis and therapy of several diseases including cancers. Various studies over the decades have signified the role of exosomes in different stages of cancer. Exosomes play a key role in colorectal cancer initiation (CRC), promotion of anti- apoptotic signaling pathways, regulating tumor microenvironment, enhancing tumorigenicity, promotion of angiogenesis, stem cell proliferation and endothelial cell migration, establishment of immune suppressive environment, formation of pre- metastatic niche and metastasis. Exosomes also elicits drug resistance. Since, they have the ability to cross the biological barrier, exosomes are now being explored as an efficient target specific drug delivery system that facilitates the shipping of different biomolecules and therapeutic drugs. However, cautious and strong investigative approaches are required before approving exosomes as therapeutics or drug delivery systems. In this review, we summarize the role of exosomes in different stages of CRC and also elaborate on the applications of exosomes in diagnosis and therapy with respect to CRC.Gliomas encompass highly invasive primary central nervous system (CNS) tumours of glial cell origin with an often-poor clinical prognosis. find more Of all gliomas, glioblastoma is the most aggressive form of primary brain cancer. Current treatments in glioblastoma are insufficient due to the invasive nature of brain tumour cells, which typically results in local tumour recurrence following treatment. The latter represents the most important cause of mortality in glioblastoma and underscores the necessity for an in-depth understanding of the underlying mechanisms. Interestingly, increased synthesis and secretion of several proteolytic enzymes within the tumour microenvironment, such as matrix metalloproteinases, lysosomal proteases, cathepsins and kallikreins for extracellular-matrix component degradation may play a major role in the aforementioned glioblastoma invasion mechanisms. These proteolytic networks are key players in establishing and maintaining a tumour microenvironment that promotes tumour cell survival, proliferation, and migration. Indeed, the targeted inhibition of these proteolytic enzymes has been a promisingly useful therapeutic strategy for glioblastoma management in both preclinical and clinical development. We hereby summarize current advances on the biology of the glioblastoma tumour microenvironment, with a particular emphasis on the role of proteolytic enzyme families in glioblastoma invasion and progression, as well as on their subsequent prognostic value as biomarkers and their therapeutic targeting in the era of precision medicine.We have recently reported that phosphatidylethanolamine (PE)-containing liposomes are endocytosed and then induce lipid droplets (LDs) in HEK293T cells. In this study, we elucidated a mechanism responsible for endocytosis of PE-containing liposomes and induction of LDs. By using fluorescence-labeled liposomes and flow cytometry, we found that PE-containing liposomes were very efficiently internalized in HEK293T cells. However, Block lipid transporter-1 (BLT-1) only marginally suppressed the uptake of these liposomes, indicating that entire liposomes were mostly taken up in these cells. They were therefore inferred to express abundant PE receptors responsible for endocytosis of PE-containing liposomes. We examined the expression of 52 candidate genes through transcriptomic analyses and eventually narrowed it down to four candidate genes, which were abundantly expressed in HEK293T cells. Among siRNAs targeting these candidates, scavenger receptor class B type 1 (SR-B1) siRNA showed the most profound reduction in PE liposomal uptake. Conversely, the expression of SR-B1 by transfection of an expression plasmid enhanced the uptake of PE-containing liposomes. After the internalization of PE-containing liposomes, they were colocalized with endosomes/lysosomes and SR-B1, which indicates that these liposomes are taken up in HEK293T cells at least partially through the endosomal/lysosomal pathway. A specific anti-SR-B1-antibody blocked the uptake of PE-containing liposomes in HEK293T cells while LD formation in these cells induced by PE-containing liposomes was suppressed by treatment with SR-B1 siRNA. These results demonstrate that SR-B1 functions as a receptor for the endocytosis of PE-containing liposomes and regulates the formation of LDs induced by PE-containing liposomes in HEK293T cells.
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