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A curcumin derivative hydrazinobenzoylcurcumin suppresses stem‐like features of glioblastoma cells by targeting Ca 2+ /calmodulin‐dependent protein kinase II
Author(s) -
Shin Hee Jeong,
Lee Sanghun,
Jung Hye Jin
Publication year - 2019
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.27972
Subject(s) - homeobox protein nanog , sox2 , cancer research , stem cell , neurosphere , cancer stem cell , signal transduction , downregulation and upregulation , gene knockdown , biology , chemistry , microbiology and biotechnology , apoptosis , cellular differentiation , transcription factor , biochemistry , adult stem cell , embryonic stem cell , gene , induced pluripotent stem cell
Glioblastoma multiforme (GBM) is the most aggressive and common type of human primary brain tumor. Glioblastoma stem‐like cells (GSCs) have been proposed to contribute to tumor initiation, progression, recurrence, and therapeutic resistance of GBM. Therefore, targeting GSCs could be a promising strategy to treat this refractory cancer. Calmodulin (CaM), a major regulator of Ca 2+ ‐dependent signaling, controls various cellular functions via interaction with multiple target proteins. Here, we investigated the anticancer effect of hydrazinobenzoylcurcumin (HBC), a Ca 2+ /CaM antagonist, against GSCs derived from U87MG and U373MG cells. HBC significantly inhibited not only the self‐renewal capacity, such as cell growth and neurosphere formation but also the metastasis‐promoting ability, such as migration and invasion of GSCs. HBC induced apoptosis of GSCs in a caspase‐dependent manner. Notably, HBC repressed the phosphorylation of Ca 2+ /CaM‐dependent protein kinase II (CaMKII), c‐Met, and its downstream signal transduction mediators, thereby reducing the expression levels of GSC markers, such as CD133, Nanog, Sox2, and Oct4. In addition, the knockdown of CaMKIIγ remarkably decreased the cancer stem cell‐like phenotypes as well as the expression of stemness markers by blocking c‐Met signaling pathway in U87MG GSCs. These results suggest that HBC suppresses the stem‐like features of GBM cells via downregulation of CaM/CaMKII/c‐Met axis and therefore CaMKII may be a novel therapeutic target to eliminate GSCs.