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Published on: January 31, 2025
Down-regulation of lipids transporter ABCA1 increases the cytotoxicity of nitidine
Hironori Iwasaki1, Takafumi Okabe, Kensaku Takara
1Center of Molecular Biosciences, Tropical Biosphere Research Center, University of the Ryukyus, Nishihara, Okinawa, Japan. hiwasaki@comb.u-ryukyu.ac.jp
Purpose:
Nitidine (NTD) cytotoxicity is highly specific for A549 human lung adenocarcinoma cells. We hypothesized that this cytotoxicity involved the accumulation of NTD in intracellular organelles. However, there have been no reports of NTD transporting factors. In this study, we screened for an NTD transporter and evaluated its association with NTD cytotoxicity.
Methods:
Gene expression analyses were done for A549 and human fetal lung normal diploid fibroblast (WI-38) cells. We screened for ABC transporter, multi-drug resistance-associated genes. Gene expressions of ATP-binding cassette transporter A1 (ABCA1) were confirmed in 8 cell lines by quantitative PCR. The involvement of ABCA1 in NTD cytotoxicity was evaluated using siRNA-mediated ABCA1 gene silencing.
Results:
Gene expression analysis indicated that A549 cells expressed higher levels of ABCC1, ABCC2, ABCC3, and ABCG2 and a lower level of ABCA1 compared to WI-38 cells. NTD resistant cell lines uniformly showed higher ABCA1 expression levels. Gene silencing experiments showed that the down-regulation of ABCA1 resulted in increased sensitivity to NTD.
Conclusions:
These results indicated that NTD efflux is controlled by ABCA1 activity, suggesting that ABCA1 transports molecules other than lipids. Thus, there is a possibility that ABCA1 acts as a drug resistance transporter involved in the cytotoxicity of NTD derivatives. This also suggested that the expression level of the ABCA1 gene may be an indicator for the efficiency of NTD treatment.
Insights
Nitidine (NTD) cytotoxicity is specific to lung cancer cells. ATP-binding cassette transporter A1 (ABCA1) regulates NTD efflux, influencing treatment efficiency and suggesting ABCA1
Area of Science:
- Molecular Biology
- Cell Biology
- Pharmacology
Background:
- Nitidine (NTD) exhibits specific cytotoxicity against A549 human lung adenocarcinoma cells.
- The mechanism of NTD cytotoxicity and its transport factors remain largely uncharacterized.
- Intracellular organelle accumulation is hypothesized to mediate NTD's cytotoxic effects.
Purpose of the Study:
- To identify NTD transporting factors.
- To investigate the role of identified transporters in NTD cytotoxicity.
- To screen for ATP-binding cassette (ABC) transporters associated with NTD resistance.
Main Methods:
- Gene expression analysis of A549 and WI-38 cells.
- Screening of multi-drug resistance-associated genes, focusing on ABC transporters.
- Quantitative PCR to confirm ATP-binding cassette transporter A1 (ABCA1) expression.
- siRNA-mediated gene silencing to assess ABCA1's role in NTD cytotoxicity.
Main Results:
- A549 cells showed higher expression of ABCC1, ABCC2, ABCC3, and ABCG2, and lower ABCA1 compared to WI-38 cells.
- NTD-resistant cell lines consistently exhibited elevated ABCA1 expression.
- Down-regulation of ABCA1 via gene silencing significantly increased sensitivity to NTD.
Conclusions:
- ATP-binding cassette transporter A1 (ABCA1) activity controls Nitidine (NTD) efflux.
- ABCA1 may function as a drug resistance transporter for NTD derivatives.
- ABCA1 gene expression levels could serve as a predictive biomarker for NTD treatment efficacy.
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