Etoposide Triggers Cellular Senescence by Inducing Multiple Centrosomes and Primary Cilia in Adrenocortical Tumor Cells
Etoposide (ETO) has been used in treating adrenocortical tumor (ACT) cells. Our previous study showed that ETO inhibits ACT cell growth. In the present study, we show that ETO treatment at IC50 (10 μM) inhibited ACT cell growth by inducing cellular senescence rather than apoptosis. Several markers o...
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MDPI AG
2021-06-01
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| author | Yen-Ni Teng Huei-Cih Chang Yu-Ying Chao Hui-Ling Cheng Wei-Chih Lien Chia-Yih Wang |
| author_facet | Yen-Ni Teng Huei-Cih Chang Yu-Ying Chao Hui-Ling Cheng Wei-Chih Lien Chia-Yih Wang |
| author_sort | Yen-Ni Teng |
| collection | DOAJ |
| description | Etoposide (ETO) has been used in treating adrenocortical tumor (ACT) cells. Our previous study showed that ETO inhibits ACT cell growth. In the present study, we show that ETO treatment at IC50 (10 μM) inhibited ACT cell growth by inducing cellular senescence rather than apoptosis. Several markers of cellular senescence, including enlarged nuclei, activated senescence-associated β-galactosidase activity, elevated levels of p53 and p21, and down-regulation of Lamin B1, were observed. We further found that ETO induced multiple centrosomes. The inhibition of multiple centrosomes accomplished by treating cells with either roscovitine or centrinone or through the overexpression of NR5A1/SF-1 alleviated ETO-induced senescence, suggesting that ETO triggered senescence via multiple centrosomes. Primary cilia also played a role in ETO-induced senescence. In the mechanism, DNA-PK-Chk2 signaling was activated by ETO treatment; inhibition of this signaling cascade alleviated multiple ETO-induced centrosomes and primary cilia followed by reducing cellular senescence. In addition to DNA damage signaling, autophagy was also triggered by ETO treatment for centrosomal events and senescence. Importantly, the inactivation of DNA-PK-Chk2 signaling reduced ETO-triggered autophagy; however, the inhibition of autophagy did not affect DNA-PK-Chk2 activation. Thus, ETO activated the DNA-PK-Chk2 cascade to facilitate autophagy. The activated autophagy further induced multiple centrosomes and primary cilia followed by triggering senescence. |
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| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T10:30:06Z |
| publishDate | 2021-06-01 |
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| spelling | doaj.art-34c015e10e0549238ea963f36251a9c72023-11-21T23:42:01ZengMDPI AGCells2073-44092021-06-01106146610.3390/cells10061466Etoposide Triggers Cellular Senescence by Inducing Multiple Centrosomes and Primary Cilia in Adrenocortical Tumor CellsYen-Ni Teng0Huei-Cih Chang1Yu-Ying Chao2Hui-Ling Cheng3Wei-Chih Lien4Chia-Yih Wang5Department of Biological Sciences and Technology, National University of Tainan, Tainan 700, TaiwanDepartment of Biological Sciences and Technology, National University of Tainan, Tainan 700, TaiwanDepartment of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan 701, TaiwanDepartment of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan 701, TaiwanDepartment of Physical Medicine and Rehabilitation, College of Medicine, National Cheng Kung University, Tainan 701, TaiwanDepartment of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan 701, TaiwanEtoposide (ETO) has been used in treating adrenocortical tumor (ACT) cells. Our previous study showed that ETO inhibits ACT cell growth. In the present study, we show that ETO treatment at IC50 (10 μM) inhibited ACT cell growth by inducing cellular senescence rather than apoptosis. Several markers of cellular senescence, including enlarged nuclei, activated senescence-associated β-galactosidase activity, elevated levels of p53 and p21, and down-regulation of Lamin B1, were observed. We further found that ETO induced multiple centrosomes. The inhibition of multiple centrosomes accomplished by treating cells with either roscovitine or centrinone or through the overexpression of NR5A1/SF-1 alleviated ETO-induced senescence, suggesting that ETO triggered senescence via multiple centrosomes. Primary cilia also played a role in ETO-induced senescence. In the mechanism, DNA-PK-Chk2 signaling was activated by ETO treatment; inhibition of this signaling cascade alleviated multiple ETO-induced centrosomes and primary cilia followed by reducing cellular senescence. In addition to DNA damage signaling, autophagy was also triggered by ETO treatment for centrosomal events and senescence. Importantly, the inactivation of DNA-PK-Chk2 signaling reduced ETO-triggered autophagy; however, the inhibition of autophagy did not affect DNA-PK-Chk2 activation. Thus, ETO activated the DNA-PK-Chk2 cascade to facilitate autophagy. The activated autophagy further induced multiple centrosomes and primary cilia followed by triggering senescence.https://www.mdpi.com/2073-4409/10/6/1466etoposidecentrosomeprimary ciliasenescenceautophagyDNA-PK |
| spellingShingle | Yen-Ni Teng Huei-Cih Chang Yu-Ying Chao Hui-Ling Cheng Wei-Chih Lien Chia-Yih Wang Etoposide Triggers Cellular Senescence by Inducing Multiple Centrosomes and Primary Cilia in Adrenocortical Tumor Cells Cells etoposide centrosome primary cilia senescence autophagy DNA-PK |
| title | Etoposide Triggers Cellular Senescence by Inducing Multiple Centrosomes and Primary Cilia in Adrenocortical Tumor Cells |
| title_full | Etoposide Triggers Cellular Senescence by Inducing Multiple Centrosomes and Primary Cilia in Adrenocortical Tumor Cells |
| title_fullStr | Etoposide Triggers Cellular Senescence by Inducing Multiple Centrosomes and Primary Cilia in Adrenocortical Tumor Cells |
| title_full_unstemmed | Etoposide Triggers Cellular Senescence by Inducing Multiple Centrosomes and Primary Cilia in Adrenocortical Tumor Cells |
| title_short | Etoposide Triggers Cellular Senescence by Inducing Multiple Centrosomes and Primary Cilia in Adrenocortical Tumor Cells |
| title_sort | etoposide triggers cellular senescence by inducing multiple centrosomes and primary cilia in adrenocortical tumor cells |
| topic | etoposide centrosome primary cilia senescence autophagy DNA-PK |
| url | https://www.mdpi.com/2073-4409/10/6/1466 |
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