Radiation-induced G2/M arrest rarely occurred in glioblastoma stem-like cells

Liu, Junfeng; Liu, Yu; Xie, Tao; Luo, Longjun; Xu, Changwu; Gao, Qinglei; Shen, Lu; Wan, Feng; Lei, Ting; Ye, Fei

doi:10.1080/09553002.2018.1440094

Cited by 9 publications

(17 citation statements)

References 39 publications

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“…We used two markers of apoptosis, cleaved-Parp and cleaved-Caspase 3, to evaluate apoptotic response after irradiation in the three GSC populations. We observed a dose-dependent increase in both cleaved-Parp and cleaved-Caspase 3 ( Fig 5D ) in GSCs, consistent with the literature [ 21 ]. There were no apparent differences in the expression levels of cleaved-Parp or cleaved-Caspase 3 between the two dose rates.…”

Section: Resultssupporting

confidence: 91%

The effects of extra high dose rate irradiation on glioma stem-like cells

et al. 2018

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Radiation therapy is an integral part of treatment for patients with glioblastoma. New technological advances in linear accelerators have made extra-high dose rate irradiation possible. This shortens patient treatment time significantly compared to standard dose rate irradiation, but the biologic effects of extra high dose rate irradiation are poorly understood. Glioma stem-like cells (GSCs) are resistant to standard radiation and contribute to tumor progression. Here, we assess the therapeutic effect of extra high dose rate vs. standard dose rate irradiation on GSCs. GSCs were exposed to 2, 4 and 6 Gy X-irradiation at dose rates of 4.2 Gy/min or 21.2 Gy/min (400 monitoring units (MU)/min or 2100 MU/min). We analyzed cell survival with cell growth assays, tumorsphere formation assays and colony formation assays. Cell kill and self-renewal were dependent on the total dose of radiation delivered. However, there was no difference in survival of GSCs or DNA damage repair in GSCs irradiated at different dose rates. GSCs exhibited significant G1 and G2/M phase arrest and increased apoptosis with higher doses of radiation but there was no difference between the two dose rates at each given dose. In a GSC-derived preclinical model of glioblastoma, radiation extended animal survival, but there was no difference in survival in mice receiving different dose rates of radiation. We conclude that GSCs respond to larger fractions of radiation, but extra high dose rate irradiation has no significant biologic advantage in comparison with standard dose rate irradiation.

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Section: Resultssupporting

confidence: 91%

The effects of extra high dose rate irradiation on glioma stem-like cells

et al. 2018

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“…13,14,31,32 However, a portion of patients suffer from resistance to radiotherapy, which characterized by continuous proliferation and tumor relapse after standard radiotherapy. 20,33 Although there has been a wealth of studies that attempt to unveil the underlying mechanisms of radioresistance, none of them can fully accommodate the issues faced by oncologist possibly due to lack of in-depth understanding of radioresistance. In the present study, we focused on radio-response of the cells from NPC, to which radiotherapy has been a first-line treatment in clinical settings.…”

Section: Discussionmentioning

confidence: 99%

Glutamine synthetase facilitates cancer cells to recover from irradiation-induced G2/M arrest

Peng

et al. 2019

Cancer Biology & Therapy

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Resistance to radiation of cancer cells can be either intrinsic or acquired, leading to treatment failure. In response to DNA damage caused by IR, cancer cells are arrested in cell cycle showing limited proliferation and increased apoptosis. However, radiation-resistant cells are able to overcome the cell cycle block and proceed to proliferation, for which the detailed mechanism remains to be elucidated. In the present study, we showed that radioresistant cells exhibited a recoverable G2/M phase during prolonged cell cycle and manifested lower apoptosis rate and more colony formation. RNA-seq analysis revealed that glutamine synthetase (GS, GLUL) gene was highly expressed in radioresistant cancer cells in comparison with the parental cells, which was in accordance with the G2/M arrest after ionizing radiation. Knocking out of GS in radioresistant cells resulted in a delayed G2/M recovery and lowered proliferation rate after ionizing radiation treatment, which was accompanied with increased inhibitory phosphorylation of CDK1 at Y15 and downregulated Cdc25B, a dual specific phosphatase of CDK1. Moreover, there was an enhanced complex formation of CDK1 and Cyclin B1 when the cells were rescued by re-introducing GS. In vivo, knocking down of GS significantly sensitized CNE2-R xenografts to RT in mice. In this study, we demonstrate a novel role of glutamine synthetase independent of metabolic function in promoting recovery from G2/M arrest caused by ionizing radiation, thus, causing cancer cell resistance to radiotherapy.

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“…The protein phosphatase Cdc25C regulates entry into mitosis by activating the Cdc2/CyclinB1 kinase complex. At the onset of mitosis, Cdc2 is dephosphorylated by Cdc25C at Threonine‐14 (Thr‐14) and Tyrosine‐15 (Tyr‐15), the Cdc2/CyclinB complex translocates into the nucleus, and the cell cycle progresses into M phase . Cdc25C and Cdc2 are both critical regulators in G2/M transition and are modulated by many factors.…”

Section: Discussionmentioning

confidence: 99%

“…30,31 Tyrosine-15 (Tyr-15), the Cdc2/CyclinB complex translocates into the nucleus, and the cell cycle progresses into M phase. 32 Cdc25C and Cdc2 are both critical regulators in G2/M transition and are modulated by many factors. Some studies have suggested that activation of the ATM/Chk1 pathway could inhibit Cdc25C activation, thereby preventing dephosphorylation of Cdc2 and entry into mitosis, as well as cell cycle arrest at the G2/M phase.…”

Section: Effect Of Ost On Er Stress Associated Protein Expression Imentioning

confidence: 99%

Osthole induced apoptosis in human normal liver cells by regulating cell proliferation and endoplasmic reticulum stress

Shen

Chen

Hong

2019

Environmental Toxicology

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Osthole (Ost) is often used in treatment for cancer, inflammation and rheumatism in clinic. However, Ost‐induced liver injury has been reported. In this study, we aim to investigate the possible mechanism of Ost‐induced hepatotoxicity in human normal liver cells (L02). When cells were exposed to Ost, the cell viability was decreased and apoptosis rate increased, the intracellular markers of oxidative stress were changed. Simultaneously, Ost altered apoptotic related proteins levels, including Bcl‐2, Bax, Cleaved‐Caspase‐9/‐8/‐3, and Pro‐Caspase‐3/‐8. In addition, Ost enhanced the levels of endoplasmic reticulum (ER) stress proteins (GRP78/Bip, CHOP, Caspase‐4, IRE1α, PERK, JNK, P‐JNK, and ATF4), decreased the cell proliferation and cycle‐associated protein (Phospho‐Histone H3, P‐Cdc25C, Cdc25C, P‐Cdc2, Cdc2, and Cyclin B1) level. The results show that Ost has toxic effects on L02 cells. Furthermore, it induces apoptosis by inhibiting cell proliferation, arresting cell cycle at the G2/M phase and activating ER stress.

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Radiation-induced G2/M arrest rarely occurred in glioblastoma stem-like cells

Abstract: We explored the cell-cycle alterations and cell-cycle-related proteins expression levels in GSLCs after irradiation, providing a novel mechanism of radioresistance of GSLCs.

Cited by 9 publications

References 39 publications

The effects of extra high dose rate irradiation on glioma stem-like cells

The effects of extra high dose rate irradiation on glioma stem-like cells

Glutamine synthetase facilitates cancer cells to recover from irradiation-induced G2/M arrest

Osthole induced apoptosis in human normal liver cells by regulating cell proliferation and endoplasmic reticulum stress

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