Intracellular cholesterol level regulates sensitivity of glioblastoma cells against temozolomide-induced cell death by modulation of caspase-8 activation via death receptor 5-accumulation and activation in the plasma membrane lipid raft

Yamamoto, Yuta; Tomiyama, Arata; Sasaki, Nobuyoshi; Yamaguchi, Hideki; Shirakihara, Takuya; Nakashima, Katsuhiko; Kumagai, Kosuke; Takeuchi, Satoru; Toyo’oka, Toshimasa; Otani, Naoki; Wada, Koichiro; Narita, Yoshitaka; Ichimura, Koichi; Sakai, Ryuichi; Namba, Hiroki; Mori, Kentaro

doi:10.1016/j.bbrc.2017.11.113

Cited by 21 publications

(35 citation statements)

References 22 publications

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“…Caspase-9 is an important effector of intrinsic or mitochondrial-regulated apoptosis 41 – 44 . It has been recently reported that TMZ induces caspase-dependent apoptosis in several cancer cells 45 , 46 . Thus, we determined the effects of TMZ-induced MOMP on caspase-9 activation.…”

Section: Resultsmentioning

confidence: 99%

Autophagy modulates temozolomide-induced cell death in alveolar Rhabdomyosarcoma cells

et al. 2018

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Rhabdomyosarcoma (RMS) is a muscle-derived tumor. In both pre-clinical and clinical studies Temozolomide (TMZ) has been recently tested against RMS; however, the precise mechanism of action of TMZ in RMS remains unclear. Here we demonstrate that TMZ decreases the cell viability of the RH30 RMS and C2C12 cell line, where cells display evidence of mitochondrial outer membrane permeability. Interestingly, the C2C12 mouse myoblast line was relatively more resistant to TMZ-induced apoptosis. Moreover, we observed that TMZ activated biochemical and morphological markers of autophagy in both cell lines. Autophagy inhibition in both RH30 and C2C12 cells significantly increased TMZ-induced cell death. In RH30 cells, TMZ increased Mcl-1 and Bax protein expression compared to corresponding time match controls while in C2C12 Mcl-1, Bcl-2, Bcl-XL, and Bax protein expression were not changed. Baf-A1 co-treatment with TMZ significantly decrease Mcl-1 expression compared to TMZ while increase Bax expression in C2C12 cells (Bcl2 and Bcl-XL do not significantly change in Baf-A1/TMZ co-treatment). Using a three-dimensional (3D) C2C12 and RH30 culture model we demonstrated that TMZ is significantly more toxic in RH30 cells (live/dead assay). Additionally, we have observed in our 3D culture model that TMZ induced both apoptosis (cleavage of PARP) and autophagy (LC3-puncta and localization of LC3/p62). Therefore, our data demonstrate that TMZ induces simultaneous autophagy and apoptosis in both RH30 and C2C12 cells in 2D and 3D culture model, where RH30 cells are more sensitive to TMZ-induced death. Furthermore, autophagy serves to protect RH30 cells from TMZ-induced death.

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Section: Resultsmentioning

confidence: 99%

Autophagy modulates temozolomide-induced cell death in alveolar Rhabdomyosarcoma cells

et al. 2018

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“…29 In contrast, Yamamoto et al reported that MCD treatment can inhibit DR5 clustering to lipid rafts and disrupt DR5-caspase-8 complex. 22 The data presented here revealed that the impact of lipids on LMP1/LMP1 interaction was negative. Lipids likely restricted LMP1 in microdomains of internal perinuclear membranes, and inhibited the formation of LMP1/LMP1 complex.…”

Section: Discussionmentioning

confidence: 54%

“…Lambert et al reported that MCD treatment can enhance viability of cells and promote cell growth, such as HaCaT cells and human glioma cells. 22,28,29 In contrast, Onodera et al reported that MCD can cause cytotoxicity in some cells, such as KB cells, Ihara cells, and M213 cells. 30 Anil et al also made an identical result in TNBC cells.…”

Section: Discussionmentioning

confidence: 96%

“…20 Additionally, lipid rafts are reported to be associated with celldeath or proliferation through reorganizing membrane receptor molecules such as G-protein coupled receptors (GPCRs). 21,22 These studies suggested that self-aggregation of LMP1 was closely associated with cell proliferation through lipid rafts. However, whether self-aggregation of LMP1 in lipid rafts can mediate LMP1/LMP1 interaction is not yet clear.…”

Section: Introductionmentioning

confidence: 99%

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Real-time detection of LMP1/LMP1 interaction in MβCD-induced apoptosis of nasopharyngeal carcinoma cells using FRET method

Huang

et al. 2019

J. Innov. Opt. Health Sci.

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Latent membrane protein 1 (LMP1) is known as an oncoprotein in nasopharyngeal carcinoma (NPC) cells, which is considered to have a strong association with growth, invasion and metastasis of NPC cells through lipid rafts. Methyl-[Formula: see text]-cyclodextrin (M[Formula: see text]CD) can disrupt lipid rafts through cholesterol depletion. In this study, we revealed that M[Formula: see text]CD induced apoptosis in two kinds of NPC cells including CNE1 cells, a LMP1-negative nasopharyngeal squamous carcinoma cell line, and CNE1-LMP1 cells, a LMP1-positive nasopharyngeal squamous carcinoma cell line. Furthermore, the impact of M[Formula: see text]CD on LMP1 was investigated by fluorescence resonance energy transfer (FRET) method in NPC cells. Synchronized tempo-spatial and spectral detection of LMP1/LMP1 interaction were performed using fluorescence microscope and spectrograph. FRET efficiency indicated that LMP1/LMP1 interaction gradually enhanced after M[Formula: see text]CD treatment. MTT assays showed that M[Formula: see text]CD caused strong cytotoxicity in CNE1 cells, but caused relatively weaker cytotoxicity in CNE1-LMP1 cells, which indicated that LMP1 may regulate sensitivity of NPC cells to M[Formula: see text]CD. Then, detection of cleaved caspase-3 in two kinds of NPC cells indicated that LMP1 may inhibit activation of caspase-3. These results strongly suggested that M[Formula: see text]CD can induce apoptosis of NPC cells, but enhancing of LMP1/LMP1 interaction may likely resist apoptosis through inhibiting cleavage of caspase-3.

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“… 48) In addition, our recent report demonstrated statins with clinical concentration rather suppress TMZ-induced GBM cell death. 49) Therefore, it is suggested the antitumor effect of statins against GBM is various and might depend on its concentration of use.…”

Section: Effects Of Simultaneous Treatment With Cholesterol Depletingmentioning

confidence: 99%

Involvement of Intracellular Cholesterol in Temozolomide-Induced Glioblastoma Cell Death

Yamamoto

Sasaki

Kumagai

et al. 2018

Neurol. Med. Chir.(Tokyo)

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Glioblastoma (GBM) still carries a poor prognosis due to the refractoriness against antitumor drugs. Temozolomide (TMZ), one of the few standard therapy drugs against GBM worldwide, has only limited effect due to acquired TMZ resistance of GBM. Therefore, development of novel therapeutic methods to overcome the TMZ resistance of GBM is urgent. The brain is the most cholesterol-rich organ in the human body, so modulation of cholesterol in tumor cells originating from the brain including GBM may be a tumor-specific therapeutic strategy including enhancement of TMZ effects. The unique lipid metabolism of glioma has recently been reported, but the involvement of intracellular cholesterol in TMZ therapy is yet to be fully elucidated. This review summarizes the effect of modulation of intracellular cholesterol level on cancer therapy including GBM treatment and the implications for TMZ therapy. Our recent findings about the involvement of intracellular cholesterol in TMZ-induced GBM cell death are described.

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Intracellular cholesterol level regulates sensitivity of glioblastoma cells against temozolomide-induced cell death by modulation of caspase-8 activation via death receptor 5-accumulation and activation in the plasma membrane lipid raft

Cited by 21 publications

References 22 publications

Autophagy modulates temozolomide-induced cell death in alveolar Rhabdomyosarcoma cells

Autophagy modulates temozolomide-induced cell death in alveolar Rhabdomyosarcoma cells

Real-time detection of LMP1/LMP1 interaction in MβCD-induced apoptosis of nasopharyngeal carcinoma cells using FRET method

Involvement of Intracellular Cholesterol in Temozolomide-Induced Glioblastoma Cell Death

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