• Genetic variation in the ABCB1 gene associated with post treatment lyme disease syndrome status

      Lyon, J.; Seung, H. (Elsevier B.V., 2019)
      Post Treatment Lyme Disease Syndrome (PTLDS) poses a difficult to understand health issue. This multi-centered, randomized control trial studied the possible correlation between ABCB1 (MDR1) gene variants and the incidence of PTLDS in affected patients. Genomic DNA was isolated and analyzed for four ABCB1 gene SNPs (rs1128503, rs1045642, rs2235067, and rs4148740). Significant findings include the association of rs1128503 TC variant with PTLDS status. Additionally, the rs1128503+ rs1045642+ rs2235067 SNP combination increased rs1128503 genotype TC significance to 3.83 times the rs1128503 genotype CC. The TT variant of rs4148740 in conjunction with rs1128503 reduced the odds ratio and appeared to convey a PTLDS protective status to the rs1128503 TC variant. Copyright 2019 The Authors
    • N6-methyladenosine-induced ERRγ triggers chemoresistance of cancer cells through upregulation of ABCB1 and metabolic reprogramming

      Chen, Z.; Wu, L.; Zhou, J. (Ivyspring International Publisher, 2020)
      Background: Drug resistance severely reduces treatment efficiency of chemotherapy and leads to poor prognosis. However, regulatory factors of chemoresistant cancer cells are largely unknown. Methods: The expression of estrogen receptor related receptors (ERRs) in chemoresistant cancer cells are checked. The roles of ERRγ in chemoresistance are confirmed by in vitro and in vivo studies. The mechanisms responsible for ERRγ-regulated expression of ABCB1 and CPT1B are investigated. Results: The expression of ERRγ is upregulated in chemoresistant cancer cells. Targeted inhibition of ERRγ restores the chemosensitivity. ERRγ can directly bind to the promoter of ABCB1 to increase its transcription. An elevated interaction between ERRγ and p65 in chemoresistant cells further strengthens transcription of ABCB1. Further, ERRγ can increase the fatty acid oxidation (FAO) in chemoresistant cells via regulation of CPT1B, the rate-limiting enzyme of FAO. The upregulated ERRγ in chemoresistant cancer cells might be due to increased levels of N6-methyladenosine (m6A) can trigger the splicing of precursor ESRRG mRNA. Conclusions: m6A induced ERRγ confers chemoresistance of cancer cells through upregulation of ABCB1 and CPT1B. Copyright The author(s).
    • Use of photoimmunoconjugates to characterize ABCB1 in cancer cells

      Liang, Barry J.; Lusvarghi, Sabrina; Ambudkar, Suresh V.; Huang, Huang Chiao (De Gruyter Open Ltd, 2021-07-26)
      Accurate detection of ATP-binding cassette drug transporter ABCB1 expression is imperative for precise identification of drug-resistant tumors. Existing detection methods fail to provide the necessary molecular details regarding the functional state of the transporter. Photoimmunoconjugates are a unique class of antibody–dye conjugates for molecular diagnosis and therapeutic treatment. However, conjugating hydrophobic photosensitizers to hydrophilic antibodies is quite challenging. Here, we devise a photoimmunoconjugate that combines a clinically approved benzoporphyrin derivative (BPD) photosensitizer and the conformational-sensitive UIC2 monoclonal antibody to target functionally active human ABCB1 (i.e., ABCB1 in the inward-open conformation). We show that PEGylation of UIC2 enhances the BPD conjugation efficiency and reduces the amount of non-covalently conjugated BPD molecules by 17%. Size exclusion chromatography effectively separates the different molecular weight species found in the UIC2–BPD sample. The binding of UIC2–BPD to ABCB1 was demonstrated in lipidic nanodiscs and ABCB1-overexpressing triple negative breast cancer (TNBC) cells. UIC2–BPD was found to retain the conformation sensitivity of UIC2, as the addition of ABCB1 modulators increases the antibody reactivity in vitro. Thus, the inherent fluorescence capability of BPD can be used to label ABCB1-overexpressing TNBC cells using UIC2–BPD. Our findings provide insight into conjugation of hydrophobic photosensitizers to conformation-sensitive antibodies to target proteins expressed on the surface of cancer cells.