Macroautophagy, (heretofore referred to as autophagy) is thought to play a pivotal role in tumorigenesis and tumor cell survival. Autophagy is a self-degradative cellular process that recycles intracellular components such as proteins and lipids, and may also be used to clear extraneous or damaged organelles. Through this process, metabolites such as amino acids or fatty acids can be liberated for use by the cell. While basal levels of autophagy are required for cellular homeostasis, autophagy is most commonly induced in response to metabolic stressors. In this way, autophagy may be utilized by cancer cells to adapt to the tumor microenvironment, which may be hypoxic and/or nutrient low, or as an adaptive response to cytotoxic insult by chemotherapeutic agents. Conversely, excessive or dysregulated autophagy may be part of the cell death pathway continuum, having been previously implicated in both apoptosis and necrosis [1, 2]. In addition, down regulation of tumor autophagy may promote immune evasion by disrupting the antigen-processing pathway [3, 4]. Therefore, further investigation of autophagy’s role in tumor cell survival and death is warranted.
Visit the following link for full text of the article: http://www.jscholaronline.org/full-text/JCRTO/103/exploring-new-strategies-to-monitor-autophagy-and-related-cell-death-pathways-using-raman-spectroscopy
ErbB4 (HER4) is a member of the ErbB family of receptor tyrosine kinases, which includes the Epidermal Growth Factor Receptor (EGFR/ErbB1), ErbB2 (HER2/Neu), and ErbB3 (HER3). Mounting evidence indicates that ErbB4, unlike EGFR or ErbB2, functions as a tumor suppressor in many human malignancies.
Previous analyses of the constitutively-dimerized and –active ErbB4 Q646C mutant indicate that ErbB4 kinase activity and phosphorylation of ErbB4 Tyr1056 are both required for the tumor suppressor activity of this mutant in human breast, prostate, and pancreatic cancer cell lines. However, the cytoplasmic region of ErbB4 possesses additional putative functional motifs, and the contributions of these functional motifs to ErbB4 tumor suppressor activity have been largely underexplored.
Here we demonstrate that ErbB4 BH3 and LXXLL motifs, which are thought to mediate interactions with Bcl family proteins and steroid hormone receptors, respectively, are required for the tumor suppressor activity of the ErbB4 Q646C mutant. Furthermore, abrogation of the site of ErbB4 cleavage by gamma-secretase also disrupts the tumor suppressor activity of the ErbB4 Q646C mutant. This last result suggests that ErbB4 cleavage and subcellular trafficking of the ErbB4 cytoplasmic domain may be required for the tumor suppressor activity of the ErbB4 Q646C mutant. Indeed, here we demonstrate that mutants that disrupt ErbB4 kinase activity, ErbB4 phosphorylation at Tyr1056, or ErbB4 cleavage by gamma-secretase also disrupt ErbB4 trafficking away from the plasma membrane and to the cytoplasm. This supports a model for ErbB4 function in which ErbB4 tumor suppressor activity is dependent on ErbB4 trafficking away from the plasma membrane and to the cytoplasm, mitochondria, and/or the nucleus.
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Aberrations in the enzymes that modify ubiquitin moieties have been observed to cause a myriad of diseases, including cancer. Therefore a better understanding of these enzymes and their substrates will lead to the identification of prospective druggable targets. Here we discuss the role of ubiquitin modifying enzymes in the canonical TGF-β pathway highlighting the ubiquitin regulating enzymes, which may potentially be targeted by small molecule inhibitors.
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Transporter proteins classified into the solute carrier (SLC) superfamily are essential for import of nutrients for cell survival in organisms. In the last two decades, compelling evidence has accumulated that SLC transporters interact with clinically important anticancer agents and contribute to their pharmacokinetics, particularly the biopharmaceutical processes of absorption, elimination and distribution. Furthermore, many SLC transporters have been shown to be differentially upregulated in cancer cells, and this may represent an adaptive response to altered nutritional requirements. Thus, it is likely to utilize them as carrier for efficient drug delivery as well as pharmacological target to shut off the nutrients essential for cell growth of malignant tumors. This short review will introduce organic anion transporting polypeptides which recognize endo- and exogenous organic anionic compounds and recent findings about their upregulation in cancer cells. Besides, OATP-mediated transport of sulfate conjugates of steroid hormone may contribute to cell survival and adapted growth under hormonedepleted conditions. Better understandings of pathophysiological role of OATPs may provide key information to overcome hormone-refractory breast and prostate tumors.
Visit the following link for full text of the article: http://www.jscholaronline.org/full-text/JCRTO/101/a-putative-role-of-organic-anion-transporting-polypeptides-(oatps)-in-cell-survival-of-hormone-dependent-breast-and-prostate-cancers
