Induction of N-Ras degradation by flunarizine-mediated autophagy

Research output: Contribution to journalArticle

Ze Yi Zheng, Jing Li, Fuhai Li, Yanqiao Zhu, Kemi Cui, Stephen T. Wong, Eric C. Chang, Yi Hua Liao

Ras GTPases are powerful drivers for tumorigenesis, but directly targeting Ras for treating cancer remains challenging. The growth and transforming activity of the aggressive basal-like breast cancer (BLBC) are driven by N-Ras. To target N-Ras in BLBC, this study screened existing pharmacologically active compounds for the new ability to induce N-Ras degradation, which led to the identification of flunarizine (FLN), previously approved for treating migraine and epilepsy. The FLN-induced N-Ras degradation was not affected by a 26S-proteasome inhibitor. Rather, it was blocked by autophagy inhibitors. Furthermore, N-Ras can be seen co-localized with active autophagosomes upon FLN treatment, suggesting that FLN alters the autophagy pathway to degrade N-Ras. Importantly, FLN treatment recapitulated the effect of N-RAS silencing in vitro by selectively inhibiting the growth of BLBC cells, but not that of breast cancer cells of other subtypes. In addition, in vivo FLN inhibited tumor growth of a BLBC xenograft model. In conclusion, this proof-of-principle study presents evidence that the autophagy pathway can be coerced by small molecule inhibitors, such as FLN, to degrade Ras as a strategy to treat cancer. FLN has low toxicity and should be further investigated to enrich the toolbox of cancer therapeutics.

Original languageEnglish (US)
Article number16932
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

PMID: 30446677

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Induction of N-Ras degradation by flunarizine-mediated autophagy. / Zheng, Ze Yi; Li, Jing; Li, Fuhai; Zhu, Yanqiao; Cui, Kemi; Wong, Stephen T.; Chang, Eric C.; Liao, Yi Hua.

In: Scientific Reports, Vol. 8, No. 1, 16932, 01.12.2018.

Research output: Contribution to journalArticle

Harvard

Zheng, ZY, Li, J, Li, F, Zhu, Y, Cui, K, Wong, ST, Chang, EC & Liao, YH 2018, 'Induction of N-Ras degradation by flunarizine-mediated autophagy' Scientific Reports, vol. 8, no. 1, 16932. https://doi.org/10.1038/s41598-018-35237-2

APA

Zheng, Z. Y., Li, J., Li, F., Zhu, Y., Cui, K., Wong, S. T., ... Liao, Y. H. (2018). Induction of N-Ras degradation by flunarizine-mediated autophagy. Scientific Reports, 8(1), [16932]. https://doi.org/10.1038/s41598-018-35237-2

Vancouver

Zheng ZY, Li J, Li F, Zhu Y, Cui K, Wong ST et al. Induction of N-Ras degradation by flunarizine-mediated autophagy. Scientific Reports. 2018 Dec 1;8(1). 16932. https://doi.org/10.1038/s41598-018-35237-2

Author

Zheng, Ze Yi ; Li, Jing ; Li, Fuhai ; Zhu, Yanqiao ; Cui, Kemi ; Wong, Stephen T. ; Chang, Eric C. ; Liao, Yi Hua. / Induction of N-Ras degradation by flunarizine-mediated autophagy. In: Scientific Reports. 2018 ; Vol. 8, No. 1.

BibTeX

@article{8189b055596a4ef8ae40a6b92e6b2308,
title = "Induction of N-Ras degradation by flunarizine-mediated autophagy",
abstract = "Ras GTPases are powerful drivers for tumorigenesis, but directly targeting Ras for treating cancer remains challenging. The growth and transforming activity of the aggressive basal-like breast cancer (BLBC) are driven by N-Ras. To target N-Ras in BLBC, this study screened existing pharmacologically active compounds for the new ability to induce N-Ras degradation, which led to the identification of flunarizine (FLN), previously approved for treating migraine and epilepsy. The FLN-induced N-Ras degradation was not affected by a 26S-proteasome inhibitor. Rather, it was blocked by autophagy inhibitors. Furthermore, N-Ras can be seen co-localized with active autophagosomes upon FLN treatment, suggesting that FLN alters the autophagy pathway to degrade N-Ras. Importantly, FLN treatment recapitulated the effect of N-RAS silencing in vitro by selectively inhibiting the growth of BLBC cells, but not that of breast cancer cells of other subtypes. In addition, in vivo FLN inhibited tumor growth of a BLBC xenograft model. In conclusion, this proof-of-principle study presents evidence that the autophagy pathway can be coerced by small molecule inhibitors, such as FLN, to degrade Ras as a strategy to treat cancer. FLN has low toxicity and should be further investigated to enrich the toolbox of cancer therapeutics.",
author = "Zheng, {Ze Yi} and Jing Li and Fuhai Li and Yanqiao Zhu and Kemi Cui and Wong, {Stephen T.} and Chang, {Eric C.} and Liao, {Yi Hua}",
year = "2018",
month = "12",
day = "1",
doi = "10.1038/s41598-018-35237-2",
language = "English (US)",
volume = "8",
journal = "Scientific Reports",
issn = "2045-2322",
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number = "1",

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RIS

TY - JOUR

T1 - Induction of N-Ras degradation by flunarizine-mediated autophagy

AU - Zheng, Ze Yi

AU - Li, Jing

AU - Li, Fuhai

AU - Zhu, Yanqiao

AU - Cui, Kemi

AU - Wong, Stephen T.

AU - Chang, Eric C.

AU - Liao, Yi Hua

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Ras GTPases are powerful drivers for tumorigenesis, but directly targeting Ras for treating cancer remains challenging. The growth and transforming activity of the aggressive basal-like breast cancer (BLBC) are driven by N-Ras. To target N-Ras in BLBC, this study screened existing pharmacologically active compounds for the new ability to induce N-Ras degradation, which led to the identification of flunarizine (FLN), previously approved for treating migraine and epilepsy. The FLN-induced N-Ras degradation was not affected by a 26S-proteasome inhibitor. Rather, it was blocked by autophagy inhibitors. Furthermore, N-Ras can be seen co-localized with active autophagosomes upon FLN treatment, suggesting that FLN alters the autophagy pathway to degrade N-Ras. Importantly, FLN treatment recapitulated the effect of N-RAS silencing in vitro by selectively inhibiting the growth of BLBC cells, but not that of breast cancer cells of other subtypes. In addition, in vivo FLN inhibited tumor growth of a BLBC xenograft model. In conclusion, this proof-of-principle study presents evidence that the autophagy pathway can be coerced by small molecule inhibitors, such as FLN, to degrade Ras as a strategy to treat cancer. FLN has low toxicity and should be further investigated to enrich the toolbox of cancer therapeutics.

AB - Ras GTPases are powerful drivers for tumorigenesis, but directly targeting Ras for treating cancer remains challenging. The growth and transforming activity of the aggressive basal-like breast cancer (BLBC) are driven by N-Ras. To target N-Ras in BLBC, this study screened existing pharmacologically active compounds for the new ability to induce N-Ras degradation, which led to the identification of flunarizine (FLN), previously approved for treating migraine and epilepsy. The FLN-induced N-Ras degradation was not affected by a 26S-proteasome inhibitor. Rather, it was blocked by autophagy inhibitors. Furthermore, N-Ras can be seen co-localized with active autophagosomes upon FLN treatment, suggesting that FLN alters the autophagy pathway to degrade N-Ras. Importantly, FLN treatment recapitulated the effect of N-RAS silencing in vitro by selectively inhibiting the growth of BLBC cells, but not that of breast cancer cells of other subtypes. In addition, in vivo FLN inhibited tumor growth of a BLBC xenograft model. In conclusion, this proof-of-principle study presents evidence that the autophagy pathway can be coerced by small molecule inhibitors, such as FLN, to degrade Ras as a strategy to treat cancer. FLN has low toxicity and should be further investigated to enrich the toolbox of cancer therapeutics.

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