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

Woo Sun Kwon, SunYoung Rha, Hei Cheul Jeung, Joong Bae Ahn, Jae Joon Jung, Dong Hyuk Ki, Tae Soo Kim, Hyuncheol Chung

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)73-84
Number of pages12
JournalBiochemical Pharmacology
Volume123
DOIs
Publication statusPublished - 2017 Jan 1

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Microtubules
Genes
Neoplasms
Cells
Microarray Analysis
Microarrays
Cell Line
Small Interfering RNA
Tubulin Modulators
Pharmaceutical Preparations
Drug Resistance
Assays
Nucleotides
Association reactions
Proteins

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

Cite this

Kwon, Woo Sun ; Rha, SunYoung ; Jeung, Hei Cheul ; Ahn, Joong Bae ; Jung, Jae Joon ; Ki, Dong Hyuk ; Kim, Tae Soo ; Chung, Hyuncheol. / ABCB1 2677G>T/A variant enhances chemosensitivity to anti-cancer agents acting on microtubule dynamics through LAMP1 inhibition. In: Biochemical Pharmacology. 2017 ; Vol. 123. pp. 73-84.
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abstract = "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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ABCB1 2677G>T/A variant enhances chemosensitivity to anti-cancer agents acting on microtubule dynamics through LAMP1 inhibition. / Kwon, Woo Sun; Rha, SunYoung; Jeung, Hei Cheul; Ahn, Joong Bae; Jung, Jae Joon; Ki, Dong Hyuk; Kim, Tae Soo; Chung, Hyuncheol.

In: Biochemical Pharmacology, Vol. 123, 01.01.2017, p. 73-84.

Research output: Contribution to journalArticle

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