The study on the regulatory mechanism of NADPH oxidase (Nox) 5alpha and 4 redox signaling involved in cancer development

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K08628
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: University of Miyazaki
• Principal Investigator: Kamata Tohru 宮崎大学, フロンティア科学実験総合センター, 客員研究員 (40056304)
• Co-Investigator(Kenkyū-buntansha): 森下 和広 宮崎大学, 医学部, 教授 (80260321) ; 中畑 新吾 宮崎大学, 医学部, 講師 (80437938)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: NADDPH oxidase(Nox) / 分子腫瘍学 / 活性酸素 / HLV-1 / すい臓がん

Outline of Final Research Achievements

The aim of this study is to investigate the signaling mechanism of NADPH oxidases (Noxs)-derived reactive oxygen species (ROS) that mediates cancer development. Our study revealed that Nox5alpha-generated H2O2 transmits signals to protein tyrosine phosphatase-1B through oxidation.Nox5alpha also promotes reprogramming of aerobic glycolysis and glutaminolysis in human T-cell leukemia virus type 1-transformed T-cells, thereby contributing to their growth. Similar results were obtained with Nox4, in which Nox4, coupled to oncogenic K-Ras, induced elevated aerobic glycolysis in pancreatic cancer cells, giving a growth advantage to the cells. Thus, these results support the notion that Nox-derived ROS play an important role in carcinogenesis and further strengthen the possibility of Nox5alpha and Nox4 as molecular targets in cancer treatment.

Free Research Field

分子腫瘍学

Academic Significance and Societal Importance of the Research Achievements

正常細胞ではNADPH oxidase酵素(Nox5alpha,Nox4)から産生される活性酸素はシグナル分子として機能している。本研究で、Nox5alphaの活性酸素はリン酸化調節蛋白にシグナルを送ることを見出した。また、これらの活性酸素がHTLV-1感染白血病やすい臓がん細胞で過剰に産生されると情報伝達を攪乱し、グルコースやグルタミン代謝の代謝調節を亢進してがん細胞の異常増殖に寄与することを明らかにした。この発見には、がん化の情報伝達の調節機構のさらなる解明と、この酵素を分子標的とした新たながん治療薬の開発につながるという意義がある。