Stmc-08. actin cytoskeleton regulator arp2/3 complex is required for dll1 activating notch1 signaling to maintain the stem cell phenotype of brain tumor initiating cells

Glioblastoma (GBM) is the most common and lethal primary intracranial tumor. Actin cytoskeleton regulator ARP2/3 complex modulates glioma cell invasion and migration. Besides, inside the tumor entity contains brain tumor initiating cells (BTICs), which are resistant to chemical and radiation therapies and form recurrent tumor. It has been shown that NOTCH signaling is essential for BTICs to maintain the stem cell phenotype. But little is known regarding the role of actin cytoskeleton in NOTCH signaling and the stem cell phenotype maintenance. Here, we show ARP2/3 complex is required for NOTCH ligand DLL1 to activate NOTCH1 signaling, thus maintaining the stem cell phenotype. CD133-positive glioma cells co-expressed NESTIN and DLL1, and exhibited high NOTCH1 activity both in specimens and in vitro U87-MG and U251-MG glioma neurospheres. Silencing DLL1 decreased NOTCH1 activity as well as BTICs markers CD133 and NESTIN expression in both glioma neurospheres. Self-renewal ability was also impaired in DLL1 knockdown cells detected through single-cell neurosphere formation assay. Both ARP2/3 complex specific inhibitor CK636 and silencing subunit ARP2 induced the same effect with DLL1 knockdown. Subcellular fractionation experiments showed that membrane protein DLL1 was less expressed on the cell membrane of ARP2/3 inhibited and knockdown cells than untreated cells. An original method was introduced to study the expression pattern among cells inside the sphere. It showed that DLL1 ...
Source: Neuro-Oncology - Category: Cancer & Oncology Authors: Tags: STEM CELLS Source Type: research