Kanazawa University research: Overcoming cancer drug resistance

KANAZAWA, Japan, April 2, 2025 /PRNewswire/ -- Researchers at Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, report in Nature Communications how the targeted suppression of lysosome function may lead to brain cancer therapy.

Glioblastoma is a type of brain cancer with a very poor prognosis of survival. Causes of glioblastoma are not known, and there is no method for preventing the cancer. Traditional treatment includes the drug temozolomide (TMZ). In many cases, TMZ kills glioblastoma cells, but a significant portion of patients show resistance to the drug. Changes in the levels of metabolites — small molecules playing key roles in metabolic processes in living organisms — have been observed in TMZ-resistant glioblastoma cells, pointing to the importance of understanding and targeting metabolic pathways in the context of cancer therapy. Now, Atushi Hirao from Kanazawa University and colleagues have investigated the role of lysosomes — cellular organelles that break down biomolecules no longer needed — in metabolic processes linked to the development of glioblastoma. Based on their findings, they propose a targeted lysosomal dysfunction strategy for the treatment of glioblastoma.

Lysosomes perform important biochemical functions. Apart from degrading 'waste' biopolymers, they are involved in cell signaling and energy flow and interact with other organelles. As such, they are also relevant for the development and growth of cancer. Hirao and colleagues first checked whether lysosome activity is an indicator of glioblastoma progression. They looked at glioblastoma cell lines taken from patients and found a correlation between lysosomal activity and glioblastoma tumorigenesis and malignancy.

The researchers then investigated how lysosomal activity affects the therapeutic efficacy of TMZ. They found that when administering lysosomal inhibitors, the sensitivity of glioblastoma to TMZ increased, confirming the critical role played by lysosomes in glioblastoma. Further experiments pointed to a protein called transcription factor E3 (TFE3) as a crucial molecule for maintaining lysosomal function, and TMZ tolerance, in glioblastoma cells.

The scientists then studied which amino acids are essential for lysosomal activity in the context of glioblastoma progression. They discovered a correlation between lysine and glioblastoma malignancy. Lysine is not produced by the human body; it must be obtained through nutrition. Hirao and colleagues therefore considered whether a lysine-restricted diet could be a therapeutic strategy for glioblastoma. They pointed out that, while lysine restriction might be a possible approach, it has limited practical use because of toxicity concerns – the human body needs lysine as a precursor to vital proteins.

Instead, the researchers worked out an alternative approach mimicking the effect of lysine restriction. Realizing that one of lysine's functions is to antagonize the effect of arginine, which plays a role in the biosynthesis of nitric oxide, they tested the use of homoarginine, an antagonist of lysine — that is, inhibiting lysine's function — to counteract lysine's blocking of nitric oxide production from arginine, and induce lysosomal dysfunction. Experiments with mice showed that the combination of TMZ and homoarginine led to a significant suppression of glioblastoma cells, demonstrating its potential therapeutic value (Figure).

The work of Hirao and colleagues highlights the critical role of lysosomal function in glioblastoma pathogenesis, and how mimicking lysin restriction may play a role in anticancer strategies. Quoting the researchers: "… disrupting lysosomal function may provide a promising avenue for glioblastoma therapy."

Background

Glioblastoma

Glioblastoma is a type of brain cancer. It starts with the growth of cells in the brain or spinal cord. The cancer grows quickly and can destroy healthy tissue. Although glioblastoma can happen at all ages, it tends to occur more in older adults. Symptoms include headaches, vomiting, nausea, blurred or double vision, difficulty with speaking, an altered sense of touch, and seizures. There is no cure for glioblastoma; treatments can slow cancer growth and reduce symptoms.

Lysosome

Lysosomes are organelles, enclosed by membranes, located within cells. They contain many types of enzymes (bioproteins with a catalytic function) that assist in breaking down many kinds of biopolymers, such as proteins, carbohydrates, and nucleic acids. As such, lysosomes serve as the 'digestive system' of the cell, degrading material from both within and outside of the cell. Lysosomes also serve as signaling hubs, lying at the junction of many metabolic pathways. Recent research has revealed that lysosomes play important roles in cancer development. Detailed understanding of metabolic pathways in the lysosome may help unlock its therapeutic potential. Atsushi Hirao from Kanazawa University and colleagues have now identified a particular lysosome function that is critical for the resistance of glioblastoma cells to the drug temozolomide, a finding that holds promise for anticancer therapies based on lysosome dysfunction.

Reference

Yongwei Jing, Masahiko Kobayashi, Mahmoud I. Shoulkamy, Meiqi Zhou, Ha Thi Vu, Hiroshi Arakawa, Hemragul Sabit, Sadahiro Iwabuchi, Cong Quang Vu, Atsuko Kasahara, Masaya Ueno, Yuko Tadokoro, Kenta Kurayoshi, Xi Chen, Yuhang Yan, Satoshi Arai, Shinichi Hashimoto, Tomoyoshi Soga, Tomoki Todo, Mitsutoshi Nakada, and Atsushi Hirao. 

Lysine-arginine imbalance overcomes therapeutic tolerance governed by the transcription factor E3-lysosome axis in glioblastoma, Nature Communications 16, 2876 (2025).

DOI: https://doi.org/10.1038/s41467-025-56946-z

URL: https://www.nature.com/articles/s41467-025-56946-z

Figure

https://nanolsi.kanazawa-u.ac.jp/wp/wp-content/uploads/Figure-7.png

Caption. Glioblastoma tumor growth in mice; comparison of TMZ administration without and with homoarginine.

© 2025 Jing, et al., Nature Communications

Funding acknowledgements

This work was supported by a Grant-in-Aid for Scientific Research (A) and (B) (grant number 19H01033 and 23H02746, to A.H.), a Grant-in-Aid for Early-Career Scientists (grant number 23K14589, to Y.J.) and a Grant-in-Aid for Scientific Research (C) (grant number 20K07566 and 23K06629, to M.K.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; and a Grant-in-Aid for Project for Promotion of Cancer Research and Therapeutic Evolution (grant number 23ama221102h0002, to A.H.) from the Japan Agency for Medical Research and Development. This work was also supported by MEXT Promotion of Development of a Joint Usage/Research System Project: Coalition of Universities for Research Excellence (CURE) Program (JPMXP1323015484) and by the World Premier International Research Center Initiative (WPI).

Kimie Nishimura (Ms)
Project Planning and Outreach, NanoLSI Administration Office
Nano Life Science Institute, Kanazawa University
Email: nanolsi-office@adm.kanazawa-u.ac.jp 

About Nano Life Science Institute (WPI-NanoLSI), Kanazawa University

Understanding nanoscale mechanisms of life phenomena by exploring "uncharted nano-realms".

Cells are the basic units of almost all life forms. We are developing nanoprobe technologies that allow direct imaging, analysis, and manipulation of the behavior and dynamics of important macromolecules in living organisms, such as proteins and nucleic acids, at the surface and interior of cells. We aim at acquiring a fundamental understanding of the various life phenomena at the nanoscale.

https://nanolsi.kanazawa-u.ac.jp/en/

About the World Premier International Research Center Initiative (WPI)

The WPI program was launched in 2007 by Japan's Ministry of Education, Culture, Sports, Science and Technology (MEXT) to foster globally visible research centers boasting the highest standards and outstanding research environments. Numbering more than a dozen and operating at institutions throughout the country, these centers are given a high degree of autonomy, allowing them to engage in innovative modes of management and research. The program is administered by the Japan Society for the Promotion of Science (JSPS).

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About Kanazawa University

As the leading comprehensive university on the Sea of Japan coast, Kanazawa University has contributed greatly to higher education and academic research in Japan since it was founded in 1949. The University has three colleges and 17 schools offering courses in subjects that include medicine, computer engineering, and humanities.

The University is located on the coast of the Sea of Japan in Kanazawa – a city rich in history and culture. The city of Kanazawa has a highly respected intellectual profile since the time of the fiefdom (1598-1867). Kanazawa University is divided into two main campuses: Kakuma and Takaramachi for its approximately 10,200 students including 600 from overseas.
http://www.kanazawa-u.ac.jp/en/