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Original Article Axl Inhibitor R428 Induces Apoptosis of Cancer Cells by Blocking Lysosomal Acidification and Recycling Independent of Axl Inhibition

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Original Article Axl Inhibitor R428 Induces Apoptosis of Cancer Cells by Blocking Lysosomal Acidification and Recycling Independent of Axl Inhibition Am J Cancer Res 2018;8(8):1466-1482 www.ajcr.us /ISSN:2156-6976/ajcr0080858 Original Article Axl inhibitor R428 induces apoptosis of cancer cells by blocking lysosomal acidification and recycling independent of Axl inhibition Fangfang Chen1,2, Qiaoling Song1,2, Qiang Yu1,2 1Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; 2University of Chinese Academy of Sciences, Beijing 100049, China Received June 5, 2018; Accepted July 9, 2018; Epub August 1, 2018; Published August 15, 2018 Abstract: R428 (BGB324) is an anti-cancer drug candidate under clinical investigation. It inhibits the receptor tyro- sine kinase Axl and induces apoptosis of many types of cancer cells, but the relationship between the two has not been well established. We investigated the molecular mechanisms of the R428-induced apoptosis and found that R428 induced extensive cytoplasmic vacuolization and caspase activation, independent of its inhibitory effects on Axl. Further analyses revealed that R428 blocked lysosomal acidification and recycling, accumulated autophago- somes and lysosomes, and induced cell apoptosis. Inhibition of autophagy by autophagy inhibitors or autophagic gene-knockout alleviated the R428-induced vacuoles formation and cell apoptosis. Our study uncovered a novel function and mechanism of R428 in addition to its ability to inhibit Axl. These data will help to better direct the ap- plication of R428 as an anti-cancer reagent. It also adds new knowledge to understand the regulation of autophagy and apoptosis. Keywords: R428, Axl, cancer cells, apoptosis, autophagy, vacuolization Introduction phosphorylation on its C-terminal docking site, Tyr821, at nanomolar concentrations [2, 3]. Axl is one of the three members of the TAM R428 is also the first Axl inhibitor to enter clini- (Tyro3, Axl, and Mer) receptor tyrosine kinase cal trials in 2014 due to its superiority in inhibit- family and plays critical roles in regulating cell ing metastases of cancer cells in vitro and in survival, proliferation, adhesion, and migration animal models. It is now in Phase I/II clinical tri- [1-3]. Overexpression or activation of Axl has als of TNBC, metastatic melanoma, and NSCLC been linked to high invasiveness and metasta- in combination with pembrolizumab, Dabra- sis of many types of cancers [2]. It has also fenib/Trametinib, or erlotinib (ClinicalTrials.gov been found to be a key player in the aquired Identifier: NCT03184571, NCT03184558, NCT- resistance of cancer cells to targeted therapies 02872259 and NCT02424617). The molecular [4]. For example, upregulation of Axl in cancer mechanisms of R428 in regulating cancer cell cells has been found to be the second most growth and metastasis however have not been prevalent mechanism of resistance to EGFR thoroughly investigated. It has been reported inhibitors in addition to the T90M mutation of that R428 induced cancer cell apoptosis [6, 7], EGFR [5]. but the role of Axl inhibition in the R428-induced apoptosis has not been clear. Because of its critical roles in cancer formation and progression, Axl has been considered as a Autophagy is a catabolic process sensitive to promising target for cancer drug development. metabolic stress and is activated to remove Small molecule inhibitors of Axl therefore have unnecessary or dysfunctional cellular compo- attracted increasing attentions. R428 (BGB- nents, including organelles and proteins, medi- 324) is one of the highly potent and frequently ated by lysosomal hydrolases and subsequently studied Axl inhibitors, which blocks Axl auto- recycled to sustain cellular metabolism [8, 9]. R428 induces cancer cell apoptosis by blocking lysosomal acidification Autophagy consists of a series of events, start- Type Culture Collection. The H1299, Bel7404, ing with an inclusion of unwanted cytoplasm H1650, 97H, Bel7402, MB231 and A549 cells into an elongating phagophore to form a dou- were cultured in RPMI1640 medium (Invitrogen) ble-membrane autophagosome, followed by with 10% FBS. The Hela, LM3, H4-LAMP1-GFP, fusion with lysosomes to generate autolys- H4-GFP-LC3, MB453, PC9, H4, MEFs and MEFs osmes, in which protein digestion occurs. At (Atg5-/-) cells were cultured in DMEM medium the end, lysosomal membrane components are (Invitrogen) with 10% FBS. The SW1116 cells extruded from autolysosomes to become “pro- were cultured in MEM medium (Invitrogen) with to-lysosomes”, which eventually reform into 10% FBS. functional lysosomes by maturation (autopha- Reagents gic lysosome reformation, ALR) [10-12]. In the course of autophagy, lysosomal function is acti- The sources of chemicals, antibodies and dyes vated after autophagosome-lysosome fusion to were as follows: maintain a highly acidic lumen (pH 4.5-5.0) for proteolysis [12]. The series events of autopha- R428 (# A8329, APExBIO), LDC1267 (# S7638, gy are highly regulated and dysregulation of Selleck), Z-VAD-FMK (# S7023, Selleck), SB- autophagy have been linked to cell apoptosis. 203580 (# S1076, Selleck), chloroquine (CQ) (# However, the roles of autophagy in apoptosis c6628, Sigma-Aldrich). Spautin-1 (C43), pyrvin- regulation are complex. On one hand, autopha- ium pamoate (PP) and bafilomycin (Baf A1) gy blocks induction of apoptosis by removing were gifts from Prof. Junying Yuan (Shanghai damaged mitochondria, pro-apoptotic proteins, Institute of Organic Chemistry, Shanghai, and ROS in certain vulnerable cells. On the China). other hand, autophagy or autophagy-related proteins may facilitate apoptosis by activating α-Tubulin (# SC-5286, Santa Cruz Biote- caspases or depleting endogenous apoptotic chnology), PARP (# 556494, BD Pharmingen inhibitors [13, 14]. The precise relationship Technical), β-actin (# P30002M, Abmart). The between autophagy and apoptosis is still an following antibodies were purchased from Cell active area of research. Signaling Technology: phosphor-Axl (# 5724), Axl (# 4566), cleaved PARP (# 9541), caspase-8 In the present study, we investigated the molec- (# 9746), caspase-9 (# 9502), Bcl-2 (# 2876), ular mechanisms of R428 in inhibiting cancer Bcl-xl (# 2762), LC3B (# 3868), SQSTM1/p62 cell growth and found that R428 caused dila- (# 8025), phospho-EGFR (# 3777), EGFR (# tion of lysosomes, blocked autophagic degra- 4267). Recombinant Human Gas6 Protein (# dation , and induced cell apoptosis, all of which 885-GSB, R&D). were independent of Axl inhibition. Our study Neutral Red (NR) (# 71028260, Sinopharm provided new information on understanding Chemical Reagent Co., Ltd.), acridine orange the activities of R428 and the relationship (Biosharp), Propidium iodide (PI) (# P4170, between autophagy and apoptosis, which will Sigma-Aldrich), Lyso-tracker Red (# C1046, help to better use R428 as an anti-cancer Beyotime). agent. Western blotting Materials and methods Western blotting was performed as previously Cell line described [18]. Immune complexes were incu- bated with Immobilon Western Chemilumine- Bel7404, SMMC7721, H4-LAMP1-GFP [15], scent HRP Substrate (Millipore) for 2-3 min, and H4-GFP-LC3 [16], MEFs and MEFs (Atg5-/-) then photographed using Darkroom Eliminator [17] were gifts from Prof. Junying Yuan (C300, AZURE biosystems). (Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Cell staining and microscopy Chemistry, Shanghai, China). LM3 was a gift from Prof. Hongyang Wang (Eastern Hepa- PI staining: Cells were plated in 1 ml medium tobiliary Surgery Institute, Shanghai, China). All at 1×105 cells/well in 12-well plates one day other cell lines were obtained from the American before use. After drug treatment, PI (1 mg/ml in 1467 Am J Cancer Res 2018;8(8):1466-1482 R428 induces cancer cell apoptosis by blocking lysosomal acidification DMSO) was added to the culture medium to a experiments. The mRNA abundances of autoph- final concentration of 1 μg/ml and real time agy-related genes were quantified by real-time images were captured at 2-hours intervals with qPCR assay. The Real-time Quantitative PCR Leica Microsystems CMS GmbH, Ernst-Leitz- Assay was performed as previously described Str. 17-37 (11525103) with rhodamine filter [21], and GAPDH was used as an endogenous settings. control. The sequences of primers are as fol- lows: human MAP1LC3, forward: 5’-AACATG- NR or AO staining: Cells were plated in 500 μl AGCGAGTTGGTCAAG-3’, reverse: 5’-GCTCGTA- 4 medium at 5×10 cells/well in 24-well plates GATGTCCGCGAT-3’; human SQSTM1/p62, for- one day before use. After drug treatment, NR ward: 5’-GCACCCCAATGTGATCTGC-3’, reverse, (28 mg/ml in DMSO) was added to culture 5’-CGCTACACAAGTCGTAGTCTGG-3’; human GA- medium to a final concentration of 28 μg/ml for PDH, forward, 5’-ACCACAGTCCATGCCATCAC-3’, 15 minutes and washed out with PBS. Phase- reverse, 5’-TCCACCACCCTGTTGCTG-3’ [22]; hu- contrast images were captured with Leica man Gas6, forward, 5’-TCTTCTCACACTGTGCTG- DMI3000 B in 10 minutes. For AO staining, AO TTGCG-3’, reverse, 5’-GGTCAGGCAAGTTCTGAA- (5 mg/ml in H O) was added to culture medium 2 CACAT-3’ [23]. to a final concentration of 5 μg/ml for 15 min- utes and then replaced with fresh medium for Statistical analyses imaging. Fluorescent images were captured with Leica DMI3000 B with GFP filter settings Data were graphically represented as mean ± [19]. SD. Statistical analyses were performed by Prism version 6.0 (GraphPad Prism Software). Immunofluorescence analysis: Immunofluore- All experiments were replicated at least 3 scence analysis was performed as previously times. described [20]. For lyso-tracker red staining, lyso-tracker
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