HSP90 inhibitor DPB induces autophagy and more effectively apoptosis in A549 cells combined with autophagy inhibitors
- 90 Downloads
In our previous study, we proved that a novel Heat shock protein 90 (HSP90) inhibitor 4-(3-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl) benzoic acid (DPB) could inhibit A549 lung cancer cell growth via inducing apoptosis. However, whether DPB affects autophagy is still unknown. Here, we investigated the effects of DPB on autophagy and the improved anti-cancer activity in A549 lung cancer cells. Aggregation of LC3-II was observed using laser scanning confocal microscopy in GFP-LC3 stably transfected U87 cells. Autophagy and apoptosis-related protein levels were examined by Western blot analysis. It is suggested that treatment with DPB (5–20 μmol/L) induced mTOR-independent autophagy in dose- and time-dependent manners. Pre-treatment A549 cells with autophagy inhibitor 3-methyladenine (3-MA, 5 mmol/L) enhanced DPB-induced apoptosis. And, DPB inhibited A549 cell growth more effectively in combination with autophagy inhibitors 3-MA (5 mmol/L) or 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-one (3BDO, 30 μmol/L). These results illustrated that as a potential and promising HSP90 inhibitor, DPB could be utilized in the treatment of cancer combined with the autophagy inhibitor.
KeywordsHSP90 inhibitor DPB A549 Autophagy Apoptosis
This work was financially supported by the Natural Science Foundation of Shandong Province (grant number ZR2016CM01), Key R&D Program of Shandong Province (grant number 2018YYSP022 and 2017YYSP029), Spring Industry Leader Talent Support Plan (grant number 2017035), and Key Products Upgrading Plan for Gold Seed Enterprises (grant number 201711175).
- Cufi S, Vazquez-Martin A, Oliveras-Ferraros C, Corominas-Faja B, Cuyas E, Lopez-Bonet E, Martin-Castillo B, Joven J, Menendez JA (2013) The anti-malarial chloroquine overcomes primary resistance and restores sensitivity to trastuzumab in HER2-positive breast cancer. Sci Rep 3:2469CrossRefGoogle Scholar
- Din FV, Valanciute A, Houde VP, Zibrova D, Green KA, Sakamoto K, Alessi DR, Dunlop MG (2012) Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. Gastroenterology 142(1504–1515):e1503Google Scholar
- Liu G, Pei F, Yang F, Li L, Amin AD, Liu S, Buchan JR, Cho WC (2017) Role of autophagy and apoptosis in non-small-cell lung cancer. Int J Mol Sci 18Google Scholar
- Rebecca VW, Massaro RR, Fedorenko IV, Sondak VK, Anderson AR, Kim E, Amaravadi RK, Maria-Engler SS, Messina JL, Gibney GT, Kudchadkar RR, Smalley KS (2014) Inhibition of autophagy enhances the effects of the AKT inhibitor MK-2206 when combined with paclitaxel and carboplatin in BRAF wild-type melanoma. Pigment Cell Melanoma Res 27:465–478CrossRefGoogle Scholar
- Solit DB, Basso AD, Olshen AB, Scher HI, Rosen N (2003) Inhibition of heat shock protein 90 function down-regulates Akt kinase and sensitizes tumors to Taxol. Cancer Res 63:2139–2144Google Scholar