Entradas por Bob

Acetylation of mitochondrial superoxide dismutase (SOD2) promotes stem cell reprogramming in breast cancer


SOD2 is a known tumor initiation suppressor. However, late-stage solid tumors display high levels of SOD2 expression.  A group of researchers spread between Chicago (IL) Milwaukee (MI) and Research Triangle Park (NC) have reported that overexpression of SOD2 causes accumulation of an acetylated form that increases mitochondrial reactive oxygen species and an increase in HIF2α activity.  

HIF2α is believed to be largely responsible for treatment failure and metastatic recurrence of breast cancer. The authors found increased SOD2 and HIF2α in metastatic lesions compared with primary tumors from the same patients.  Their results suggest that the accumulation of acetylated SOD2 in later stages of cancer may promote cancer stem cell formation, leading to elevated tumor aggressiveness and poorer patient outcomes.

Antibody mediated blockage of matrix metalloproteinase 9 (MMP9) stops breast cancer metastases in mouse model


Metastasis is the principal cause of cancer-related death and has traditionally been viewed as a late-occurring process during cancer progression.  Researchers from UCSF (San Francisco) and the Weizmann Institute of Science (Rehovot, Israel) found that MMP9 is an important component of metastasis early in tumorigenesis and promotes circulating tumor cells to colonize the lungs.

In a mouse model of breast cancer, the authors found that blocking active MMP9, using a monoclonal antibody inhibited lung metastases.  The inhibition of MMP9 attenuated migration, invasion, and colony formation and promoted CD8+ T cell infiltration and activation.  Interestingly, primary tumor burden was unaffected, suggesting a role for MMP9 specific to an early phase of metastasis.

This research suggests that metastases may be disrupted early on by inhibiting active MMP9 and suggesting that a MMP9-targeted anti-metastatic breast cancer therapy may be a viable therapeutic direction to stop breast cancer metastasis.

Inhibition of USP27X deubiquitinase destabilizes Snail1 renders breast and pancreas tumor cells sensitive to chemotherapy


Epithelial-to-mesenchymal transition (EMT) is controlled by a transcriptional factor called Snail1 in cancer cells.  EMT is when epithelial cells lose their cell polarity and cell-cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells that can differentiate into a variety of cell types

Snail1 is short-lived in normal epithelial cells as a consequence of its coordinated and continuous ubiquitination by several F-box–specific E3 ligases.  The degradation of Snail-1 by F-box–specific E3 ligases is prevented in cancer cells.  The authors, based in in Spain and the US, identified USP27X as a deubiquitinase that stabilizes Snail1.

USP27X deubiquitinase depletion reduced Snail1-dependent cell migration and invasion and metastasis formation, increasing cellular sensitivity to cisplatin treatment.  These results indicate that USP27X is an essential enzyme controlling Snail1 expression and function, opening up potential new therapeutic strategies for the inhibition of Snail1 expression and its protumoral actions.