<scp>IMPDH</scp> and <scp>GTP</scp> Metabolism in Cancer: Mechanisms, Regulation, and Translational Scope
Guanosine triphosphate (GTP) is increasingly recognized as a critical actor in cancer cell proliferation, yet its regulatory mechanism remains incompletely defined. A key contributor to elevated GTP levels in tumors is inosine monophosphate dehydrogenase 2 (IMPDH2), a rate-limiting enzyme in the de novo guanine nucleotide biosynthetic pathway. Although IMPDH inhibitors, mycophenolic acid (MPA) and mycophenolate mofetil (MMF), have shown potential in cancer therapies, their success has been limited due to their immunosuppressive side effects and several unresolved regulatory mechanisms, including paradoxical control of IMPDH activity by GTP. This review provides a systematic summary of the current understanding of IMPDH biology, emphasizing its complex regulation and therapeutic relevance in cancer. We will outline key unresolved questions, including isozyme-specific roles and mechanisms for escaping regulation, and propose mechanistic and translational strategies to design IMPDH-targeted cancer therapies.
Authors
- Iemasa Koh (ORCID: https://orcid.org/0000-0003-4617-1377)
- Tomoyuki Mizuno (ORCID: https://orcid.org/0000-0002-8471-9826)
- Takao Hinoi (ORCID: https://orcid.org/0000-0003-0462-6177)
- Aki Iio (ORCID: https://orcid.org/0000-0003-4507-5228)
- Koh Takeuchi (ORCID: https://orcid.org/0000-0002-6227-4627)
- Manabu Natsumeda (ORCID: https://orcid.org/0000-0003-3098-8323)
- Tomoharu Yasuda (ORCID: https://orcid.org/0000-0001-9997-6852)
- Hiroaki Niitsu (ORCID: https://orcid.org/0000-0001-6878-9712)
- Rintaro Hashizume (ORCID: https://orcid.org/0000-0002-9373-7831)
- Natsuki Osaka
- Masashi Oshima (ORCID: https://orcid.org/0000-0002-7365-1491)
- Yujiro Ota
- Tomohiro Ishikawa (ORCID: https://orcid.org/0000-0002-0539-7372)
- Kensuke Tateishi (ORCID: https://orcid.org/0000-0001-6895-9013)
- Toshiya Senda (ORCID: https://orcid.org/0000-0002-5153-928X)
- Satoru Osuka
- Michelle Jane Genoveso (ORCID: https://orcid.org/0009-0003-4659-3585)
- Keita Shigemi
- Atsuo T. Sasaki (ORCID: https://orcid.org/0000-0003-2963-4501)
- Susumu Goyama (ORCID: https://orcid.org/0000-0002-9339-1826)
- K. Yamane
Institutions
- Hiroshima University (JP)
- Cincinnati Children's Hospital Medical Center (US)
- High Energy Accelerator Research Organization (JP)
- Jichi Medical University (JP)
- Sojo University (JP)
- The Graduate University for Advanced Studies, SOKENDAI (JP)
- Keio University (JP)
- University of Alabama at Birmingham (US)
- LTT Bio-Pharma (Japan) (JP)
- Hiroshima University Hospital (JP)
- Jichi Medical University Saitama Medical Center (JP)
- Niigata University (JP)
- National Institute of Advanced Industrial Science and Technology (JP)
- The University of Tokyo (JP)
- Yokohama City University (JP)
- University of Cincinnati Medical Center (US)
Publication Details
- Journal
- Cancer Science
- Published
- 2025-10-03
- DOI
- https://doi.org/10.1111/cas.70200
- Primary Topic
- Biochemical and Molecular Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Naito Foundation
- Japan Agency for Medical Research and Development
- Keio University
- National Institutes of Health
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency
- Core Research for Evolutional Science and Technology