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Review
. 2018 Jul 15;58(7):296-302.
doi: 10.2176/nmc.ra.2018-0040. Epub 2018 Jun 13.

Involvement of Intracellular Cholesterol in Temozolomide-Induced Glioblastoma Cell Death

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Free PMC article
Review

Involvement of Intracellular Cholesterol in Temozolomide-Induced Glioblastoma Cell Death

Yutaro Yamamoto et al. Neurol Med Chir (Tokyo). .
Free PMC article

Abstract

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.

Keywords: glioblastoma; intracellular cholesterol level; temozolomide.

Conflict of interest statement

Conflicts of Interest Disclosure

We have no potential conflicts of interest. All authors have registered online Self-reported COI Disclosure Statement Forms through the website for JNS members.

Figures

Fig. 1.
Fig. 1.
Intracellular cholesterol level regulates the sensitivity of glioblastoma (GBM) cells against temozolomide (TMZ; 400 μM)-induced cell death. (A) Intracellular cholesterol levels of TMZ-sensitive clone of U251 MG human GBM cell line (U251-Con cells) continuously treated by vehicle (dimethyl sulfoxide) and clone of U251-Con cells with acquired TMZ resistance after continuous TMZ treatment (U251-R cells) showing that total intracellular cholesterol was significantly lower in U251-R cells compared with U251-Con cells. (B) In vitro intracellular cholesterol measurement after TMZ, methyl-beta-cyclodextrin (MaCD; 0.5 mM) or water-soluble cholesterol (Chol; 20 μg/ml) treatment showing intracellular cholesterol level was upregulated by single TMZ treatment and fluctuated according to addition of MaCD and Chol. (C) Under the same conditions, cell death rate and immunoblotting of cleavage of lamin A/C showed almost the same trends as intracellular cholesterol level of U251-Con cells. (D) Combination of TMZ and Chol dramatically enhanced cell death induction in U251-R cells compared with single TMZ treatment. lamin A/C: apoptosis marker cleaved by active effector caspases. *P < 0.01. Reproduced with permission from the Biochem Biophys Res Commun (495: 1292–1299, 2018)©2018, Elsevier B.V49).
Fig. 2.
Fig. 2.
Death receptor 5 (DR5)-mediated extrinsic apoptotic pathway. See text for details. Apo2L: Apo-2 ligand, TRAIL: tumor necrosis factor-related apoptosis-inducing ligand, FADD: Fas-associated death domain, DISC: death-inducing signaling complex.
Fig. 3.
Fig. 3.
Illustration of the cholesterol-mediated enhancement mechanism of temozolomide (TMZ)-induced glioblastoma (GBM) cell death. TMZ and increase of intracellular cholesterol level induces up-regulation of DR5 expression and accumulation into plasma membrane lipid raft (➀ and ➁) followed by activation of DR5. Upon activation of DR5, extrinsic apoptosis pathway (see Fig. 2) is subsequently triggered ➂. Upregulation of intracellular cholesterol level might also re-sensitize GBM cells with acquired TMZ resistance which intracellular cholesterol level is lowered compared with before acquisition of TMZ resistance to TMZ treatment through DR5-mediated activation of extrinsic apoptosis pathway ➃. On the contrary, methyl-beta-cyclodextrin (MaCD) or statins with physiological plasma concentration reduces intracellular cholesterol level followed by inhibition of TMZ-induced GBM cell death through suppression of DR5 activation ➄. As the machinery of TMZ- or intracellular cholesterol loading-induced DR5 expression and activation, endoplasmic reticulum (ER) stress is suggested ➅.

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