Triple
negative breast cancer (TNBC) is difficult to treat due
to lack of druggable targets. We have found that treatment with the
small molecule inhibitor KPT-9274 inhibits growth of TNBC cells and
eventually leads to cell death. KPT-9274 is a dual specific inhibitor
of PAK4 and Nicotinamide Phosphoribosyltransferase (NAMPT). The PAK4
protein kinase is often highly expressed in TNBC cells and has important
roles in cell growth, survival, and migration. Previously we have
found that inhibition of PAK4 leads to growth inhibition of TNBC cells
both in vitro and in vivo. Likewise, NAMPT has been shown to be dysregulated
in cancer due to its role in cell metabolism. In order to understand
better how treating cells with KPT-9274 abrogates TNBC cell growth,
we carried out an RNA sequencing of TNBC cells treated with KPT-9274.
As a result, we identified Rictor as an important target that is inhibited
in the KPT-9274 treated cells. Conversely, we found that Rictor is
predicted to be activated when PAK4 is overexpressed in cells, which
suggests a role for PAK4 in the regulation of Rictor. Rictor is a
component of mTORC2, one of the complexes formed by the serine/threonine
kinase mTOR. mTOR is important for the control of cell growth and
metabolism. Our results suggest a new mechanism by which the KPT-9274
compound may block the growth of breast cancer cells, which is via
inhibition of mTORC2 signaling. Consistent with this, sequencing analysis
of PAK4 overexpressing cells indicates that PAK4 has a role in activation
of the mTOR pathway.
Background: Climbing fibers (CFs) innervate Purkinje cells (PCs) with 1:1 relationship to ensure proper cerebellar function. Although CFs abnormally extend into the parallel fiber domain of PC dendrites in essential tremor (ET), the architecture of CFs in relation to PCs has yet to be investigated in detail. Objective: The aim of this work was to study the architecture of CFs in relation to PCs in ET. Methods: The number of PC somas and PC dendrites that a single CF crossed was quantified in the postmortem cerebellum of 15 ET cases and 15 control cases.Results: In ET, CFs crossed a greater number of PC somas and PC dendrites than in control cases, raising the possibility that there is abnormal CF wiring onto the PCs. Interestingly, the increase in CF-PC crossings positively correlated with tremor severity. Conclusions: Patients with ET have increased CF crossings on PC dendrites. This abnormal architectural arrangement may contribute to synchronous brain activity and tremor.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.