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Biomaterials. 2017 Oct;141:188-198. doi: 10.1016/j.biomaterials.2017.07.002. Epub 2017 Jul 4.

Liposomal honokiol induced lysosomal degradation of Hsp90 client proteins and protective autophagy in both gefitinib-sensitive and gefitinib-resistant NSCLC cells.

Author information

1
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
2
Department of Thyroid and Breast Surgery, West China Hospital of Sichuan University, Chengdu, China.
3
Department of Ultrasonic Medicine, West China Second Hospital, Sichuan University, Chengdu, China.
4
Department of Respiratory Medicine, West China Hospital, Sichuan University, Chengdu, China.
5
School of Pharmacy, Chengdu University of TCM, The Ministry of Education Key Laboratory of Standardization of Chinese Herbal Medicine, State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu, China. Electronic address: wanli8801@163.com.
6
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China. Electronic address: chenlijuan125@163.com.

Abstract

Honokiol (HK), a natural chemical isolated from Mangnolia officinalis, has shown antitumorigenic activities when used to treat a variety of tumor cell lines. The mechanism of honokiol activity when used to treat gefitinib-sensitive and gefitinib-resistant non-small cell lung cancer (NSCLC) requires elucidation. Here, the presence of liposomal honokiol (LHK) induced apoptotic and antitumor activities in four xenograft models generated using NSCLC cell lines such as HCC827 (gefitinib-sensitive) and H1975 (gefitinib-resistant). Mechanistic studies revealed that LHK inhibited the Akt and Erk1/2, both EGFR signaling cascades effectors, by promoting degradation of HSP90 client proteins (HCP), including wild-type or mutant EGFR, Akt and C-Raf. Molecular biology assays showed that LHK induced HCP degradation through a lysosomal pathway, rather than the canonical proteasome protein degradation pathway. As a result of misfolded protein accumulation, LHK induced endoplasmic reticulum (ER) stress and autophagy. Inhibition of ER stress (with 4-phenylbutyrate) or autophagy (with small interfering RNA) reduced LHK-induced HCP degradations. Additionally, LHK induced autophagy showed a protective role for cancer cell as inhibition of autophagy in vitro and in vivo by autophagosome degradation inhibitors could promote the anticancer activity of LHK. LHK has been approved by the China Food and Drug Administration for first-in-human clinical trials in NSCLC. The current study will guide the design of future LHK clinical trials.

KEYWORDS:

Autophagy; EGFR; Gefitinib-resistance; HSP90; Honokiol

[Indexed for MEDLINE]

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