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ABCB1 2677G>T/A variant enhances chemosensitivity to anti-cancer agents acting on microtubule dynamics through LAMP1 inhibition

 Woo Sun Kwon  ;  Sun Young Rha  ;  Hei-Cheul Jeung  ;  Joong Bae Ahn  ;  Jae-Joon Jung  ;  Dong Hyuk Ki  ;  Tae Soo Kim  ;  Hyun Cheol Chung 
 Biochemical Pharmacology, Vol.123 : 73-84, 2017 
Journal Title
 Biochemical Pharmacology 
Issue Date
ATP Binding Cassette Transporter, Sub-Family B/genetics ; ATP Binding Cassette Transporter, Sub-Family B/physiology ; Antineoplastic Agents/pharmacology* ; Cell Line, Tumor ; Gene Knockdown Techniques ; Humans ; Lysosome-Associated Membrane Glycoproteins/antagonists & inhibitors* ; Lysosome-Associated Membrane Glycoproteins/genetics ; Microtubules/metabolism* ; Pharmacogenetics ; RNA, Small Interfering/genetics
ABCB1 ; Chemosensitivity ; LAMP1 ; Variant
Overexpression of ABCB1 associated with single nucleotide variants in cancers was reported to encode a protein responsible for drug resistance. We studied chemosensitivity-related genes associated with ABCB1 2677G>T/A variant. The associated genes were identified based on the results of the significance analysis of microarray, and then prediction accuracy was evaluated using the prediction analysis of microarray. Functional assay of the selected gene was performed by using siRNA and drug accumulation study. A higher frequency of chemoresistance to microtubule-modulating agents was found in cell lines with wild-type ABCB1 compared to cell lines with 2677G>T/A ABCB1 variant. Based on the pharmacogenetic association study with 2677 variant, we identified seven genes that could predict chemosensitivity to microtubule dynamics modulators. The classification accuracy with these seven genes was 90.0%, and the predicted probability was 0.73. LAMP1 was the only gene that was commonly related to chemosensitivity. LAMP1 expression levels were relatively higher in chemoresistant ABCB1 wild-type compared to chemosensitive polymorphic cells. But, there was no difference in ABCB1 expression levels between the two groups. Following LAMP1 siRNA, chemosensitivity was restored due to increased intracellular drug accumulation in wild type cell line. In conclusion, ABCB1 2677G>T/A variant enhances chemosensitivity on microtubule dynamics through LAMP1 inhibition.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
김태수(Kim, Tae Soo)
라선영(Rha, Sun Young) ORCID logo https://orcid.org/0000-0002-2512-4531
안중배(Ahn, Joong Bae) ORCID logo https://orcid.org/0000-0001-6787-1503
정현철(Chung, Hyun Cheol) ORCID logo https://orcid.org/0000-0002-0920-9471
정희철(Jeung, Hei Cheul) ORCID logo https://orcid.org/0000-0003-0952-3679
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