2019 Fiscal Year Annual Research Report
Translational applications of broad spectrum natural compounds and phytochemicals or their derivatives to the novel treatment strategy against sarcomas
| Project/Area Number |
15K10455
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| Research Institution | Nara Medical University |
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Principal Investigator |
朴木 寛弥 奈良県立医科大学, 医学部, 教授 (40336863)
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| Co-Investigator(Kenkyū-buntansha) |
藤井 宏真 奈良県立医科大学, 医学部, 学内講師 (00625791)
辻内 俊文 近畿大学, 理工学部, 教授 (10254492)
藤間 保晶 奈良県立医科大学, 医学部, 研究員 (60448777)
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| Project Period (FY) |
2015-04-01 – 2020-03-31
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| Keywords | sarcoma / metabolism / mitochondria / glycolysis / phytochemicals / c-myc / cancer stem cells |
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| Outline of Annual Research Achievements |
In the current research, we have found that pterostilbene (PTE), a natural compound of phytochemical, inhibits cell growth through stem cell phenotype suppression in osteosarcoma (OS) cells in vitro and revealed that the mechanism of this effect was the cause of suppression mitochondrial oxidative metabolism (OXPHOS) that cancer stem cells metabolize predominantly rather than glycolysis. We further investigated the detailed mechanisms of the mitochondrial metabolism and found that PTE suppressed Complex V activity which resulted in decrease of oxygen consumption and ATP production and increase of 4-Hydroxynonenal and ROS generation, which could inhibit cellular growth and survival.
In addition, c-myc inhibitors of JQ1 and Honokiol decreased c-Myc expression and reduced cell viability of OS cells in combination with PTE.
The current fiscal year, we have focused on PDZD8 which is involved in ER-mitochondria tethering restricting ROS generation in mitochondria, and knockdown of PDZD8 showed enhanced the effect of cell growth inhibition and increased ROS generation by PTE in OS cells. Furthermore, mesenchymal stem cells co-cultured with osteosarcoma cells showed their mitochondria transfer to OS cells under the stress of cytotoxic agents like doxorubicin and cisplatinum.
These current results lead the novel treatment targeting dual metabolic inhibition against osteosarcoma.
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