Abstract
Monopolar spindle 1 (MPS1) is an essential spindle assembly checkpoint (SAC) kinase involved in determining spindle integrity. Beyond its mitotic functions, it has been implicated in several other signaling pathways. Our earlier studies have elaborated on role of MPS1 in glioblastoma (GBM) radiosensitization. In this study using reverse phase protein arrays (RPPAs), we assessed MPS1 mediated cell signaling pathways and demonstrated that inhibiting MPS1 could upregulate the expression of the tumor suppressor PDCD4 and MSH2 genes, by down regulating micro RNA-21 (miR-21). In GBMs miR-21 expression is significantly elevated and is associated with chemo and radioresistance. Both MPS1 and miR-21 depletion suppressed GBM cell proliferation, whereas, ectopic expression of miR-21 rescued GBM cell growth from MPS1 inhibition. Further, we demonstrate that MPS1 mediates phosphorylation of SMAD3 but not SMAD2 in GBM cells; A possible mechanism behind miR-21 modulation by MPS1. Collectively, our results shed light onto an important role of MPS1 in TGF-β/SMAD signaling via miR-21 regulation. We also, show the prognostic effect of miR-21, PDCD4 and MSH2 levels to patient survival across different GBM molecular subtypes. This scenario in which miR-21 is modulated by MPS1 inhibition may be exploited as a potential target for effective GBM therapy.
Highlights
Glioblastoma multiforme or glioblastoma (GBM) continues to be the most frequently diagnosed and lethal primary brain tumor
We identified two tumor suppressor genes Programmed cell death 4 (PDCD4) and MutS homolog 2 (MSH2) within the dataset associated with micro RNA-21 (miR-21) and elevated under Monopolar spindle 1 (MPS1) inhibition (Sup Figure 1A, 1B)
These results suggest a probable role of MPS1 in regulation of tumor suppressor PDCD4, MSH2, which are direct targets of oncogenic miR-21
Summary
Glioblastoma multiforme or glioblastoma (GBM) continues to be the most frequently diagnosed and lethal primary brain tumor. MPS1 mitotic kinase is an evolutionary conserved protein kinase that is overexpressed in several human cancers and most widely functions in cell cycle control, including mitotic spindle assembly checkpoint activation, proper mitotic progression, centrosome duplication, chromosome alignment, error correction of kinetochore-microtubule attachment, and recruitment of SAC components to kinetochores [6, 7]. It is located predominantly in the cytoplasm during interphase and relocates to the nucleus late in G2 phase and associates with the kinetochore from prophase to metaphase [8, 9]
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