As part of the JST Targeted Basic Research Program, Anti-cancer therapies including radiation, embolization and chemotherapy, render cancer cells less susceptible to these therapeutic interventions, while the whole mechanisms remain to be revealed. This study paid attention to roles of stress-inducible carbon monoxide (CO) which is generated from cancer cells to increase resistance to chemotherapy. Mechanisms by which CO protects against oxidative stress or exposure to anti-cancer reagents involve a shift of utilization of glucose towards pentose phosphate pathway rather than simple glycolysis that allows cancer cells to enhance NADPH generation that is necessary to increase the ratio between reduced and oxidized glutathiones (GSH/GSSG), and ribose synthesis that is necessary to maintain proliferation, while maintaining minimum energy metabolism. Cystathionine beta-synthase, a CO-sensitive heme enzyme that rate-limits transsulphuration pathway modulates the balance of glucose utilization between glycolysis and pentose phosphate pathway through mechanisms involving regulation of methylation of PFKFB3, a key regulator of the metabolic shift. Interventions towards PFKFB3 methylation might serve as a potentially beneficial strategy to increase chemosensitivity of different types of cancer cells.
The Exploratory Research for Advanced Technology(ERATO)
“Suematsu Gas Biology Project”
Takehiro Yamamoto, Naoharu Takano, Kyoko Ishiwata, Mitsuyo Ohmura, Yoshiko Nagahata,
Tomomi Matsuura, Aki Kamata, Kyoko Sakamoto, Tsuyoshi Nakanishi, Akiko Kubo,
Takako Hishiki and Makoto Suematsu.
“Reduced methylation of PFKFB3 in cancer cells shunts glucose towards the pentose phosphate pathway.” Nature Communications, 2014
Makoto Suematsu Ph.D.
Professor, School of Medicine, Keio University
Takehiro Yamamoto Ph.D.
Assistant Professor, School of Medicine, Keio University
Department of Research Project, Japan Science and Technology Agency (JST),