ABCB1 2677G>T/A variant enhances chemosensitivity to anti-cancer agents acting on microtubule dynamics through LAMP1 inhibition.
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.
Song-Dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea.
Woo Sun
WS
Kwon
Song-Dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea; Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea; Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.
Sun Young
SY
Rha
Song-Dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea; Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea; Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
Hei-Cheul
HC
Jeung
Song-Dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea; Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea; Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
Joong Bae
JB
Ahn
Song-Dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea.
Jae-Joon
JJ
Jung
Song-Dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea.
Dong Hyuk
DH
Ki
Song-Dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea.
Tae Soo
TS
Kim
Song-Dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea; Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea; Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address: unchung8@yuhs.ac.
Hyun Cheol
HC
Chung
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000502:physiology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D006801:Humans; D051907:Lysosomal Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D008870:Microtubules / Q000378:metabolism*; D010597:Pharmacogenetics; D034741:RNA, Small Interfering / Q000235:genetics; D052118:Lysosomal-Associated Membrane Protein 1
D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D051907:Lysosomal Membrane Proteins; D034741:RNA, Small Interfering; C513055:ABCB1 protein, human; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1
ABCB1; Chemosensitivity; LAMP1; Variant