MKP1 mediates resistance to therapy in HER2-positive breast tumors.

Mitogen-activated protein kinase phosphatase 1 (MKP1 or DUSP1) is an antiapoptotic phosphatase that is overexpressed in many cancers, including breast cancer. MKP1 expression is inducible in radiation-treated breast cancer cells, and correlates with human epidermal growth factor receptor 2 (ERBB2, HER2) expression. The role of MKP1 in therapy resistance suggests that targeting MKP1 in HER2-positive breast tumors may significantly enhance the efficacy of anti-HER2 and other anticancer therapies

Nanoparticles for live cell microscopy: A surface-enhanced Raman scattering perspective.

Surface enhanced Raman scattering (SERS) nanoparticles are an attractive alternative to fluorescent probes for biological labeling because of their photostability and multiplexing capabilities. However, nanoparticle size, shape, and surface properties are known to affect nanoparticle-cell interactions. Other issues such as the formation of a protein corona and antibody multivalency interfere with the labeling properties of nanoparticle-antibody conjugates. Hence, it is important to consider these aspects in order to validate such conjugates for live cell imaging applications. Using SERS nanoparticles that target HER2 and CD44 in breast cancer cells, we demonstrate labeling of fixed cells with high specificity that correlates well with fluorescent labels. However, when labeling live cells to monitor surface biomarker expression and dynamics, the nanoparticles are rapidly uptaken by the cells and become compartmentalized into different cellular regions. This behavior is in stark contrast to that of fluorescent antibody conjugates. This study highlights the impact of nanoparticle internalization and trafficking on the ability to use SERS nanoparticle-antibody conjugates to monitor cell dynamics

Low-Level Saturated Fatty Acid Palmitate Benefits Liver Cells by Boosting Mitochondrial Metabolism via CDK1-SIRT3-CPT2 Cascade.

Saturated fatty acids (SFAs) (the "bad" fat), especially palmitate (PA), in the human diet are blamed for potential health risks such as obesity and cancer because of SFA-induced lipotoxicity. However, epidemiological results demonstrate a latent benefit of SFAs, and it remains elusive whether a certain low level of SFAs is physiologically essential for maintaining cell metabolic hemostasis. Here, we demonstrate that although high-level PA (HPA) indeed induces lipotoxic effects in liver cells, low-level PA (LPA) increases mitochondrial functions and alleviates the injuries induced by HPA or hepatoxic agent carbon tetrachloride (CCl4). LPA treatment in mice enhanced liver mitochondrial activity and reduced CCl4 hepatotoxicity with improved blood levels of aspartate aminotransferase (AST), alanine transaminase (ALT), and mitochondrial aspartate transaminase (m-AST). LPA-mediated mitochondrial homeostasis is regulated by CDK1-mediated SIRT3 phosphorylation, which in turn deacetylates and dimerizes CPT2 to enhance fatty acid oxidation. Thus, an advantageous effect is suggested by the consumption of LPA that augments mitochondrial metabolic homeostasis via CDK1-SIRT3-CPT2 cascade

MnSOD in oxidative stress response-potential regulation via mitochondrial protein influx.

SignificanceThe mitochondrial antioxidant manganese superoxide dismutase (MnSOD) is encoded by genomic DNA and its dismutase function is fully activated in the mitochondria to detoxify free radical O2(•-) generated by mitochondrial respiration. Accumulating evidence shows an extensive communication between the mitochondria and cytoplasm under oxidative stress. Not only is the MnSOD gene upregulated by oxidative stress, but MnSOD activity can be enhanced via the mitochondrial protein influx (MPI).Recent advancesA cluster of MPI containing cytoplasmic/nuclear proteins, such as cyclins, cyclin-dependent kinases, and p53 interact with and alter MnSOD activity. These proteins modulate MnSOD superoxide scavenging activity via post-translational modifications in the mitochondria. In addition to well-established pathways in gene expression, recent findings suggest that MnSOD enzymatic activity can also be enhanced by phosphorylation of specific motifs in mitochondria. This review attempts to discuss the pre- and post-translational regulation of MnSOD, and how these modifications alter MnSOD activity, which induces a cell adaptive response to oxidative stress.Critical issuesMnSOD is biologically significant to aerobic cells. Its role in protecting the cells against the deleterious effects of reactive oxygen species is evident. However, the exact network of MnSOD-associated cellular adaptive reaction to oxidative stress and its post-translational modifications, especially its enzymatic enhancement via phosphorylation, is not yet fully understood.Future directionsThe broad discussion of the multiple aspects of MnSOD regulation, including gene expression, protein modifications, and enzymatic activity, will shed light onto the unknown mechanisms that govern the prosurvival networks involved in cellular and mitochondrial adaptive response to genotoxic environment

MnSOD in oxidative stress response-potential regulation via mitochondrial protein influx.

SignificanceThe mitochondrial antioxidant manganese superoxide dismutase (MnSOD) is encoded by genomic DNA and its dismutase function is fully activated in the mitochondria to detoxify free radical O2(•-) generated by mitochondrial respiration. Accumulating evidence shows an extensive communication between the mitochondria and cytoplasm under oxidative stress. Not only is the MnSOD gene upregulated by oxidative stress, but MnSOD activity can be enhanced via the mitochondrial protein influx (MPI).Recent advancesA cluster of MPI containing cytoplasmic/nuclear proteins, such as cyclins, cyclin-dependent kinases, and p53 interact with and alter MnSOD activity. These proteins modulate MnSOD superoxide scavenging activity via post-translational modifications in the mitochondria. In addition to well-established pathways in gene expression, recent findings suggest that MnSOD enzymatic activity can also be enhanced by phosphorylation of specific motifs in mitochondria. This review attempts to discuss the pre- and post-translational regulation of MnSOD, and how these modifications alter MnSOD activity, which induces a cell adaptive response to oxidative stress.Critical issuesMnSOD is biologically significant to aerobic cells. Its role in protecting the cells against the deleterious effects of reactive oxygen species is evident. However, the exact network of MnSOD-associated cellular adaptive reaction to oxidative stress and its post-translational modifications, especially its enzymatic enhancement via phosphorylation, is not yet fully understood.Future directionsThe broad discussion of the multiple aspects of MnSOD regulation, including gene expression, protein modifications, and enzymatic activity, will shed light onto the unknown mechanisms that govern the prosurvival networks involved in cellular and mitochondrial adaptive response to genotoxic environment