Role of lymphocyte-specific protein tyrosine kinase (LCK) in the expansion of glioma-initiating cells by fractionated radiation.
Brain cancers frequently recur or progress as focal masses after treatment with ionizing radiation. Radiation used to target gliomas may expand the cancer stem cell population and enhance the aggressiveness of tumors; however, the mechanisms underlying the expansion of cancer stem cell population after radiation have remained unclear. In this study, we show that LCK (lymphocyte-specific protein tyrosine kinase) is involved in the fractionated radiation-induced expansion of the glioma-initiating cell population and acquisition of resistance to anticancer treatments. Fractionated radiation caused a selective increase in the activity of LCK, a Src family non-receptor tyrosine kinase. The activities of other Src family kinases Src, Fyn, and Lyn were not significantly increased. Moreover, knockdown of LCK expression with a specific small interfering RNA (siRNA) effectively blocked fractionated radiation-induced expansion of the CD133(+) cell population. siRNA targeting of LCK also suppressed fractionated radiation-induced expression of the glioma stem cell marker proteins CD133, Nestin, and Musashi. Expression of the known self-renewal-related proteins Notch2 and Sox2 in glioma cells treated with fractionated radiation was also downregulated by LCK inhibition. Moreover, siRNA-mediated knockdown of LCK effectively restored the sensitivity of glioma cells to cisplatin and etoposide. These results indicate that the non-receptor tyrosine kinase LCK is critically involved in fractionated radiation-induced expansion of the glioma-initiating cell population and decreased cellular sensitivity to anticancer treatments. These findings may provide pivotal insights in the context of fractionated radiation-based therapeutic interventions in brain cancer.
Department of Chemistry, Research Institute for Natural Sciences, Hanyang University, Seoul, South Korea.
Rae-Kwon
RK
Kim
Chang-Hwan
CH
Yoon
Kyung-Hwan
KH
Hyun
Hyejin
H
Lee
Sungkwan
S
An
Myung-Jin
MJ
Park
Min-Jung
MJ
Kim
Su-Jae
SJ
Lee
D001932:Brain Neoplasms / Q000201:enzymology / Q000473:pathology* / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D005910:Glioma / Q000201:enzymology / Q000473:pathology* / Q000532:radiotherapy*; D006801:Humans; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000096:biosynthesis* / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000201:enzymology* / Q000473:pathology / Q000528:radiation effects*; D034741:RNA, Small Interfering / Q000235:genetics; D011836:Radiation Tolerance
D034741:RNA, Small Interfering; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)