Increased expression of ABCB6 enhances protoporphyrin IX accumulation and photodynamic effect in human glioma.
BACKGROUND
Glioma recurrence usually occurs close to the tumor resection margins as a result of residual infiltrating glioma cells. 5-aminolevulinic acid (ALA) fluorescence-guided resection of gliomas has been demonstrated to enhance discrimination of tumor tissue and to improve survival. ALA-based photodynamic therapy is an effective albeit still experimental adjuvant treatment option for gliomas. However, insufficient protoporphyrin IX (PpIX) accumulation may limit the benefits of fluorescence-guided resection and photodynamic therapy.


METHODS
We investigated the expression of the ATP-binding cassette transporter ABCB6, which regulates porphyrin synthesis, in surgical specimens from human gliomas and manipulated ABCB6 in human glioma cell lines.


RESULTS
Our findings demonstrated that expression levels of ABCB6 were greatly elevated in human gliomas compared with normal brain tissues and correlated with World Health Organization histologic grade. A previously undescribed finding was that ABCB6 mRNA expression in solidly fluorescing tumor tissues was higher than that in vaguely fluorescing tumors, suggesting that ABCB6 may be at least in part responsible for PpIX accumulation in glioma cells. Accordingly, ABCB6 overexpression in glioma cell lines caused a marked increase in intracellular levels of PpIX, and was more sensitive to ALA-induced photodynamic therapy-events that could be prevented by silencing ABCB6 via siRNA treatment.


CONCLUSIONS
Our findings indicate a crucial role of ABCB6 in ALA metabolism and accumulation of PpIX in glioma. ABCB6 overexpression is a potential approach to enhance accumulation of PpIX for optimizing the subjective discrimination of vague fluorescence and improving the efficacy of ALA-based photodynamic therapy.
Department of Neurosurgery, The First Clinical College of Harbin Medical University, Harbin, People's Republic of China, guangsz@hotmail.com.
Shi-Guang
SG
Zhao
Xiao-Feng
XF
Chen
Li-Gang
LG
Wang
Guang
G
Yang
Da-Yong
DY
Han
Lei
L
Teng
Ming-Chun
MC
Yang
Da-Yong
DY
Wang
Chen
C
Shi
Yao-Hua
YH
Liu
Bing-Jie
BJ
Zheng
Chang-Bin
CB
Shi
Xu
X
Gao
Nikolai G
NG
Rainov
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000622:Aminolevulinic Acid / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D016022:Case-Control Studies; D049109:Cell Proliferation; D005453:Fluorescence; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D006801:Humans; D008027:Light; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000494:pharmacology; D011524:Protoporphyrins / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
C107991:ABCB6 protein, human; D018528:ATP-Binding Cassette Transporters; D017319:Photosensitizing Agents; D011524:Protoporphyrins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX