2023 Fiscal Year Research-status Report
The role of mitophagy in the reversal of senescent cancer stem cells
| Project/Area Number |
23KF0268
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| Research Institution | Nagasaki University |
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Principal Investigator |
李 桃生 長崎大学, 原爆後障害医療研究所, 教授 (50379997)
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| Co-Investigator(Kenkyū-buntansha) |
YAN CHEN 長崎大学, 原爆後障害医療研究所, 外国人特別研究員
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| Project Period (FY) |
2023-11-15 – 2026-03-31
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| Keywords | Cancer stem cells / Mitophagy / Senescence |
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| Outline of Annual Research Achievements |
Human HCT116 colorectal cancer cells were used in this study. To induce cellular senescence, HCT116 cells were treated with doxorubicin. At 7 days after doxorubicin treatment, HCT116 cells were stained strongly positive for senescence-associated β-galactosidase, suggesting the induction of senescent cells. Furthermore, the expression of p21, one of the most well-established senescence markers, was significantly higher in the doxorubicin-induced senescent HCT116 cells than in the untreated HCT116 cells. In the meantime, doxorubicin treatment also significantly inhibited the growth of HCT116 cells.
The expression of DNA damage indicators and cell cycle regulators are also determined. The expression of γH2AX, cyclin D1, and cyclin E1 were significantly higher in the doxorubicin-induced senescent HCT116 cells than in the untreated HCT116 cells, indicating enhanced DNA damage and cell cycle arrest in the doxorubicin-induced senescent HCT116 cells.
To investigate the reversibility, doxorubicin-induced senescent HCT116 cells were cultured in the medium without doxorubicin. Interestingly, some senescent HCT116 cells return to a proliferative state after 7 days of culture. Our data indicate the high plasticity of senescent cancer cells.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
Our data showed that doxorubicin treatment induced cellular senescence in the HCT116 cells. Moreover, the doxorubicin-induced senescent HCT116 cells were able to return into a proliferative state. About the detailed mechanism, we have also started to investigate, such as DNA damage and cell cycle arrest.
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| Strategy for Future Research Activity |
To further understand the role of mitophagy in regulating the plasticity of senescent cancers, we will:
1. Evaluate the mitophagy activity, mitochondrial function, and energy metabolism activity.
2. Confirm the role of mitophagy in regulating the reversal of senescent cancer cells by manipulating mitophagy activity.
3. Verify the effects of mitophagy-associated molecules in regulating the reversal of senescent cancer cells in mouse tumor models by evaluating the mitophagy activity and senescent/proliferative populations of cancer cells.
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| Causes of Carryover |
As some existing reagents and antibodies in our department were used in this study, it resulted in an incurring amount to be used next fiscal year.
The incurring amount will be used for the cost of antibodies and kits for biochemical analysis to be carried out in the next fiscal year.
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