Insights into post-transcriptional regulation of drug-metabolizing enzymes for next-generation pharmacotherapy
RNA editing and the 2019 Haazami Female Researcher Award
Miki Nakajima is the recipient of the prestigious 2019 Haazami Female Researcher Award in recognition for her research on drug metabolism and contributions to the promotion of drug discovery and drug applications.
In this research Nakajima and her colleagues focused on dihydrofolate reductase (DHFR), an enzyme known to play a central role in the metabolism of folate—also known as vitamin B-9, which is essential for the growth of healthy red and white blood cells and production of DNA and RNA. Furthermore, DHFR is targeted by methotrexate, a drug used to treat certain kinds of cancer such as breast and skin cancer. Notably, too much cellular DHFR leads to the resistance of tumors to the action of methotrexate, thereby severely limiting its therapeutic effects.
Notably, mechanisms governing methotrexate resistance are not clear. “Reports on mechanisms responsible for DHFR expression include gene amplification and microRNA-mediated post-transcriptional repression,” explains Nakajima. “We decided to look into the possibility of the role of RNA editing in the regulatory mechanism.” Specifically, Nakajima and her colleagues focused on the possibility of modulating DHFR expression with adenosine-to-inosine RNA editing, in which adenosine deaminase acting on RNA (ADAR) enzymes cause nucleotide conversion.
“We found that the knockdown of ADAR1 led to a decrease in cell viability and an increase in the sensitivity of MCF-7 cells to methotrexate through a decrease in DHFR expression,” says Nakajima. “This means that DHFR is post-transcriptionally regulated through ADAR1-mediated RNA editing, affecting cell proliferation and sensitivity of breast cancer cells to methotrexate. The results indicate that ADAR1 could be a potential anti-cancer target in treatments based on the use of anti-folate compounds including methotrexate. We published these results in the Journal of Biological Chemistry in 2017.”
Nakajima plans to use the powerful atomic force microscope technology at NanoLSi for the visualization of three-dimensional complexes formed of proteins (targets) and peptide aptamers to elucidate the possibility of developing ‘molecular targeted drugs’.
Women in science and academic research
“It is an honor to receive the 2019 Haazami Female Researcher Award,” says Nakajima. “The award was for the research on A-to-I RNA Editing that we published in 2017. It has inspired me to work even harder on realizing the goals of my research at the NanoLSI.”
Nakajima says that she had to reflect and think hard about her career options after completing her master degree at Hokkaido University’s Graduate School of Pharmaceutical Sciences. “In Japan, the majority of students graduating with degrees in pharmacy go onto careers in pharmacy or pharmaceutical company,” says Nakajima. “But I wanted to know more about pharmaceutical sciences. So after deliberating my options I decided to move onto Showa University as an assistant professor.
Later, Nakajima’s first connection with Kanazawa University was when she enrolled as an assistant professor in 1997; this laid the foundations of her research on drug metabolism. “My advisor’s group was very supportive,” says Nakajima. “I think the leader of the group, research environment, and good networking and communications skills are important factors for successful careers in research.”
Now, Nakajima is the leader of her own research group at the NanoLSI and is using her experience to inspire and nurture the leaders of the future.
- Miki Nakajima and Tsuyoshi Yokoi, “MicroRNAs from biology to future pharmacotherapy: Regulation of cytochrome P450s and nuclear receptors”, Pharmacology & Therapeutics, 131, pp. 330-337 (2011).
- Masataka Nakano, Tatsuki Fukami, Saki Gotoh and Miki Nakajima, “A-to-I RNA editing up-regulates human dihydrofolate reductase in breast cancer”, Journal of Biological Chemistry, 292, 4873–4884 (2017).
- Masataka Nakano and Miki Nakajima, “Significance of A-to-I RNA editing of transcripts modulating pharmacokinetics and pharmacodynamics”, Pharmacology & Therapeutics, 181, pp.13-21 (2018).
Miki Nakajima, NanoLSI
School of Pharmacy, Kanazawa University