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Inhibition of glioma growth by minocycline is mediated through endoplasmic reticulum stress-induced apoptosis and autophagic cell death.
Neuro Oncol. 2013 Sep; 15(9):1127-41.NO

Abstract

BACKGROUND

We have reported that minocycline (Mino) induced autophagic death in glioma cells. In the present study, we characterize the upstream regulators that control autophagy and switch cell death from autophagic to apoptotic.

METHODS

Western blotting and immunofluorescence were used to detect the expressions of eukaryotic translation initiation factor 2α (eIF2α), transcription factor GADD153 (CHOP), and glucose-regulated protein 78 (GRP78). Short hairpin (sh)RNA was used to knock down eIF2α or CHOP expression. Autophagy was assessed by the conversion of light chain (LC)3-I to LC3-II and green fluorescent protein puncta formation. An intracranial mouse model and bioluminescent imaging were used to assess the effect of Mino on tumor growth and survival time of mice.

RESULTS

The expression of GRP78 in glioma was high, whereas in normal glia it was low. Mino treatment increased GRP78 expression and reduced binding of GRP78 with protein kinase-like endoplasmic reticulum kinase. Subsequently, Mino increased eIF2α phosphorylation and CHOP expression. Knockdown of eIF2α or CHOP reduced Mino-induced LC3-II conversion and glioma cell death. When autophagy was inhibited, Mino induced cell death in a caspase-dependent manner. Rapamycin in combination with Mino produced synergistic effects on LC3 conversion, reduction of the Akt/mTOR/p70S6K pathway, and glioma cell death. Bioluminescent imaging showed that Mino inhibited the growth of glioma and prolonged survival time and that these effects were blocked by shCHOP.

CONCLUSIONS

Mino induced autophagy by eliciting endoplasmic reticulum stress response and switched cell death from autophagy to apoptosis when autophagy was blocked. These results coupled with clinical availability and a safe track record make Mino a promising agent for the treatment of malignant gliomas.

Authors+Show Affiliations

Institute of Basic Medical Sciences, Division of Neurosurgery, Department of Surgery, National Cheng-Kung University Hospital, Tainan, Taiwan.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23787763

Citation

Liu, Wei-Ting, et al. "Inhibition of Glioma Growth By Minocycline Is Mediated Through Endoplasmic Reticulum Stress-induced Apoptosis and Autophagic Cell Death." Neuro-oncology, vol. 15, no. 9, 2013, pp. 1127-41.
Liu WT, Huang CY, Lu IC, et al. Inhibition of glioma growth by minocycline is mediated through endoplasmic reticulum stress-induced apoptosis and autophagic cell death. Neuro Oncol. 2013;15(9):1127-41.
Liu, W. T., Huang, C. Y., Lu, I. C., & Gean, P. W. (2013). Inhibition of glioma growth by minocycline is mediated through endoplasmic reticulum stress-induced apoptosis and autophagic cell death. Neuro-oncology, 15(9), 1127-41. https://doi.org/10.1093/neuonc/not073
Liu WT, et al. Inhibition of Glioma Growth By Minocycline Is Mediated Through Endoplasmic Reticulum Stress-induced Apoptosis and Autophagic Cell Death. Neuro Oncol. 2013;15(9):1127-41. PubMed PMID: 23787763.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of glioma growth by minocycline is mediated through endoplasmic reticulum stress-induced apoptosis and autophagic cell death. AU - Liu,Wei-Ting, AU - Huang,Chih-Yuan, AU - Lu,I-Chen, AU - Gean,Po-Wu, Y1 - 2013/06/20/ PY - 2013/6/22/entrez PY - 2013/6/22/pubmed PY - 2014/3/22/medline KW - ER stress KW - apoptosis KW - autophagy KW - glioma KW - minocycline SP - 1127 EP - 41 JF - Neuro-oncology JO - Neuro Oncol VL - 15 IS - 9 N2 - BACKGROUND: We have reported that minocycline (Mino) induced autophagic death in glioma cells. In the present study, we characterize the upstream regulators that control autophagy and switch cell death from autophagic to apoptotic. METHODS: Western blotting and immunofluorescence were used to detect the expressions of eukaryotic translation initiation factor 2α (eIF2α), transcription factor GADD153 (CHOP), and glucose-regulated protein 78 (GRP78). Short hairpin (sh)RNA was used to knock down eIF2α or CHOP expression. Autophagy was assessed by the conversion of light chain (LC)3-I to LC3-II and green fluorescent protein puncta formation. An intracranial mouse model and bioluminescent imaging were used to assess the effect of Mino on tumor growth and survival time of mice. RESULTS: The expression of GRP78 in glioma was high, whereas in normal glia it was low. Mino treatment increased GRP78 expression and reduced binding of GRP78 with protein kinase-like endoplasmic reticulum kinase. Subsequently, Mino increased eIF2α phosphorylation and CHOP expression. Knockdown of eIF2α or CHOP reduced Mino-induced LC3-II conversion and glioma cell death. When autophagy was inhibited, Mino induced cell death in a caspase-dependent manner. Rapamycin in combination with Mino produced synergistic effects on LC3 conversion, reduction of the Akt/mTOR/p70S6K pathway, and glioma cell death. Bioluminescent imaging showed that Mino inhibited the growth of glioma and prolonged survival time and that these effects were blocked by shCHOP. CONCLUSIONS: Mino induced autophagy by eliciting endoplasmic reticulum stress response and switched cell death from autophagy to apoptosis when autophagy was blocked. These results coupled with clinical availability and a safe track record make Mino a promising agent for the treatment of malignant gliomas. SN - 1523-5866 UR - https://www.unboundmedicine.com/medline/citation/23787763/Inhibition_of_glioma_growth_by_minocycline_is_mediated_through_endoplasmic_reticulum_stress_induced_apoptosis_and_autophagic_cell_death_ L2 - https://academic.oup.com/neuro-oncology/article-lookup/doi/10.1093/neuonc/not073 DB - PRIME DP - Unbound Medicine ER -