Tumor-initiating cells contribute to radiation resistance in primary human renal clear cell carcinomas by activating the DNA damage checkpoint response

Li, Bo; Gao, Yongju; Wu, Xinyu; Cui, Jing; Long, Ya‐Qiu; Xu, Jibin; Ding, Degang

doi:10.3892/ol.2017.6504

Cited by 4 publications

(3 citation statements)

References 31 publications

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“…During the cell cycle, various checkpoints play an important role in monitoring and regulating the progression as well as the genomic stability in response to DNA damage or other stresses. Li et al reported that radiation induces G 2 /M phase arrest in primary human renal clear cell carcinoma cells, which might contribute to radioresistance 8 . Carruthers et al found that the suppression of ATM kinase, an upstream kinase of the G 2 /M checkpoint signal pathway involving CHK2/CDC25C/CDK1, by the inhibitor KU-55933 inactivates the G 2 /M checkpoint and radiosensitizes glioblastoma stem-like cells 9 .…”

Section: Introductionmentioning

confidence: 99%

BECN1 promotes radiation-induced G2/M arrest through regulation CDK1 activity: a potential role for autophagy in G2/M checkpoint

et al. 2020

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Authophagy and G2/M arrest are two important mechanistic responses of cells to ionizing radiation (IR), in particular the IR-induced fibrosis. However, what interplayer and how it links the autophagy and the G 2 /M arrest remains elusive. Here, we demonstrate that the autophagy-related protein BECN1 plays a critical role in ionizing radiation-induced G 2 /M arrest. The treatment of cells with autophagy inhibitor 3-methyladenine (3-MA) at 0–12 h but not 12 h postirradiation significantly sensitized them to IR, indicating a radio-protective role of autophagy in the early response of cells to radiation. 3-MA and BECN1 disruption inactivated the G 2 /M checkpoint following IR by abrogating the IR-induced phosphorylation of phosphatase CDC25C and its target CDK1, a key mediator of the G 2 /M transition in coordination with CCNB1. Irradiation increased the nuclear translocation of BECN1, and this process was inhibited by 3-MA. We confirmed that BECN1 interacts with CDC25C and CHK2, and which is mediated the amino acids 89–155 and 151–224 of BECN1, respectively. Importantly, BECN1 deficiency disrupted the interaction of CHK2 with CDC25C and the dissociation of CDC25C from CDK1 in response to irradiation, resulting in the dephosphorylation of CDK1 and overexpression of CDK1. In summary, IR induces the translocation of BECN1 to the nucleus, where it mediates the interaction between CDC25C and CHK2, resulting in the phosphorylation of CDC25C and its dissociation from CDK1. Consequently, the mitosis-promoting complex CDK1/CCNB1 is inactivated, resulting in the arrest of cells at the G 2 /M transition. Our findings demonstrated that BECN1 plays a role in promotion of radiation-induced G2/M arrest through regulation of CDK1 activity. Whether such functions of BECN1 in G2/M arrest is dependent or independent on its autophagy-related roles is necessary to further identify.

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Section: Introductionmentioning

confidence: 99%

BECN1 promotes radiation-induced G2/M arrest through regulation CDK1 activity: a potential role for autophagy in G2/M checkpoint

et al. 2020

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“…The radiotherapy will simultaneously damage the normal tissue or organ when killing tumor cells. On addition, the tumor has certain resistance to radiation (Li et al, 2017). This greatly hinders the improvement of the cure rate of OSCC.…”

Section: Introductionmentioning

confidence: 99%

Matrine from Vietnamese sophora root inhibits the growth of oral squamous cell carcinoma cells in vitro and in vivo

Lin

Deng

et al. 2019

Food Sci. Technol

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This study investigated the extraction of matrine from Vietnamese sophora root and its in vitro and in vivo inhibitory effects on oral squamous cell carcinoma (OSCC) cells. Matrine was extracted from Vietnamese sophora root using microwave-assisted extraction technology and purified using macroporous adsorption resin. Human OSCC Tca8113 cells were treated with matrine with concentration of 0, 0.5, 1, 2, 4 and 8 g/L. The proliferation and apoptosis of cells were detected. OSCC cells were transplanted in the nude mice, and then the nude mice were treated with normal saline, cyclophosphamide (CTX) (20 mg·kg -1 ) and matrine (100 mg·kg -1 ), respectively. The optimized extraction parameters of matrine were obtained. The in vitro experiments showed that, matrine inhibit the proliferation of Tca8113 cells and induced the cell apoptosis. The in vivo experiments found that, the tumor inhibition rate of matrine was basically equivalent to that of CTX. On addition, compared with CTX, matrine had no obvious toxic side effect on the liver and kidney function of nude mice. These results indicate that, matrine has obvious in vitro and in vivo inhibitory effects on OSCC cells, with no obvious toxic side effect on the liver and kidney function.Keywords: extraction; matrine; oral squamous cell carcinoma. Practical Application: Matrine can be extracted from Vietnamese sophora root, and may be used to treat oral squamous cell carcinoma.

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“…It is now well recognized that the initiation, the maintenance and the recurrence of tumors is sustained by Cancer Stem Cells (CSCs), a small cell population with stem-like properties identified in several solid tumors [ 8 – 10 ]. In particular, in RCC, a CSC population has been identified by expression of surface endoglin (CD105) [ 11 – 15 ].…”

Section: Introductionmentioning

confidence: 99%

Human liver stem cell-derived extracellular vesicles enhance cancer stem cell sensitivity to tyrosine kinase inhibitors through Akt/mTOR/PTEN combined modulation

et al. 2018

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It is well recognized that Cancer Stem Cells (CSCs) sustain the initiation, the maintenance and the recurrence of tumors. We previously reported that extracellular vesicles (EVs) derived from human liver stem cells (HLSCs) were able to limit tumor development. In this study, we evaluated whether EV derived from HLSCs could act in synergy with tyrosine kinase inhibitors (TKIs) on apoptosis of CSCs isolated from renal carcinomas. For this purpose, we administered to renal CSCs, HLSC-EVs and TKIs, as co-incubation or sequential administration. We found that HLSC-EVs in combination with Sunitinb or Sorafenib significantly increased renal CSCs apoptosis induced by low TKI dose. At variance, no synergistic effect was observed when bone marrow mesenchymal stem cell-derived EVs were used. In particular, renal CSCs chemosensitivity to TKIs was enhanced when HLSC-EVs were either co-administered with TKIs or added after, but not before. CSC apoptosis was also incremented at a percentage comparable to that of co-administration when TKIs were loaded in HLSC-EVs. By a mechanistic point of view, Akt/mTOR and Erk and Creb intracellular pathways, known to be pivotal in the induction of tumor growth and survival, appeared modulated as consequence of TKIs/HLSC-EVs co-administration. Together, our results indicate that the synergistic effect of HLSC-EVs with TKIs may increase the response to TKIs at low doses, providing a rational for their combined use in the treatment of renal carcinoma.

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Tumor-initiating cells contribute to radiation resistance in primary human renal clear cell carcinomas by activating the DNA damage checkpoint response

Cited by 4 publications

References 31 publications

BECN1 promotes radiation-induced G2/M arrest through regulation CDK1 activity: a potential role for autophagy in G2/M checkpoint

BECN1 promotes radiation-induced G2/M arrest through regulation CDK1 activity: a potential role for autophagy in G2/M checkpoint

Matrine from Vietnamese sophora root inhibits the growth of oral squamous cell carcinoma cells in vitro and in vivo

Human liver stem cell-derived extracellular vesicles enhance cancer stem cell sensitivity to tyrosine kinase inhibitors through Akt/mTOR/PTEN combined modulation

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