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Supplementary Figure Legends Figure S1. Azelastine Inhibits the Proliferation of CRC Cells with No Toxic Effects in Mice. (A) Co

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Supplementary Figure Legends Figure S1. Azelastine Inhibits the Proliferation of CRC Cells with No Toxic Effects in Mice. (A) Co Supplementary Figure Legends Figure S1. Azelastine inhibits the proliferation of CRC cells with no toxic effects in mice. (A) Comparison of colony formation ability of HT29, DLD1 and HCT116 cells treated with indicated concentrations of azelastine. (B) Soft agar colony formation. (C) Body weight of nude mice. (D) Representative images of the liver, kidney and lung tissues stained with hematoxylin and eosin (H & E). Bars, SD; *, P < 0.05; **, P < 0.001. Figure S2. Analysis of differentially expressed proteins in azelastine-treated HT29 cells by PLGEM. (A) PLGEM fitting of the abundance of azelastine-regulated proteins. (B) Q–Q plot of the residual versus standard normal. (C) Residual distribution along with the rank of mean abundances. (D) Histogram of residuals of identified proteins. Figure S3. Azelastine induces mitochondrial dysfunction in CRC cells. Western blotting was performed to determine the expression of Bcl-xL, Bax, and Bcl-2 in HT29 and DLD1 cells treated with indicated concentrations of azelastine for 48 h. Figure S4. Activation of the ERK pathway significantly abrogates the effect of azelastine on mitochondria. (A) Immunofluorescent staining was carried out with MitoTracker® probe to compare the morphology of mitochondria in the azelastine- treated HT29 and DLD1 cells. (B) p-ERK expression was detected by Western blotting. (C-F) CRC cells overexpressing MEK were treated with indicated concentrations of azelastine for 48 h. WST-1, immunofluorescent staining, and Western blotting were performed to compare cell viability (D), morphology of mitochondria (E), and p-Drp1 expression (F). (G) Comparison of anti-proliferation ability of azelastine and Rotenone in HT29 and DLD1 cells. Bars, SD; *, P < 0.05; **, P < 0.01. Figure S5. ARF1, but not HRH1, mediates the anticancer effect of azelastine. (A) HRH1-deficient CRC cell lines were established. (B) WST-1 assay was used to measure cell viability in HRH1-deficient CRC cell lines treated with various concentrations of azelastine. (C) Experimental schema of DARTS technology to identify the direct target of azelastine. (D) ARF1-deficient CRC cell lines were established. (E) WST-1 assay was used to measure cell viability in ARF1-deficient HT29 and DLD1cells treated with various concentrations of azelastine. (F) HT29 and DLD1 cells were treated with Mdivi-1 (10μM) for 6 h, then treated with azelastine (20μM); WST-1 assay was used to compare the cell viability. Bars, SD; *, P < 0.05; **, P < 0.01. Figure S6. ARF1 exerts its oncogenic function through ERK signaling. (A) Successful establishment of ARF1-overexpressing HCT116 and RKO cells. (B) WST- 1 assay was performed to determine cell proliferation rate in ARF1-overexpressing CRC cells and control cells. (C) The abilities of ARF1-overexpressing HCT116 and RKO cells as well as control cells to form colonies were examined. (D) Comparison of anchorage-independent growth ability by soft agar assay. (E-H) Comparison of p-ERK expression (E), cell proliferation rate (H), anchorage-dependent growth ability (F) and anchorage-independent growth ability (G) in ARF1-overexpressing CRC cells in the presence or absence of U0126 (5 μM), and the control cells. (I) Successful establishment of inducible knockdown of ARF1 in HT29 and DLD1 cells. (J-L) Effect of ARF1 knockdown on proliferation (J) and anchorage-independent growth of HT29 and DLD1 cells (K). (L) Comparison of the morphology of mitochondria in ARF1- knockdown HT29 and DLD1 cells and control cells. Bars, SD; *, P < 0.05. Bars, SD; *, P < 0.05; **, P < 0.01; ***, P < 0.001. Figure S7. Clinical significance of ARF1. (A) Comparison of ARF1 expression in 20 pairs of CRC tumors and adjacent normal tissues. (B) Data from starBase v3.0 showed that the expression of ARF1 was higher in various cancers than normal tissues. (C) Data from TCGA and GEO databases indicated that ARF1 expression was correlated with poor survival in various cancers. Bars, SD; *, P < 0.05; **, P < 0.01; ***, P < 0.001. Figure S8. Azelastine does not regulate ARF6 expression or activity in CRC cells. The expression and activity of ARF6 in HT29 and DLD1 cells treated with different concentrations of azelastine for 48 h were measured. Figure S9. Azelastine directly binds to ARF1. (A) Comparison of ARF1 expression and activity in the azelastine-treated tumor xenografts. (B) Biacore assay showed that ARF1 binds to azelastine with a Kd of 1.74 x 10-9. (C) Biacore assay showed that ARF1- T48S mutant binds to azelastine with a significantly increased Kd of 5.94 x 10-7. A B 200μm 200μm Azelastine (μM) 0 0 2.5 5 10 20 40 M) 200μm μ 200μm e ( e HT29 in st 5 D1 Azela DL 200μm 200μm 10 HCT116 HT29 DLD1 150 150 150 Azelastine (μM) 100 150 100 100 0 * ** * 10 50 50 50 20 y number (%) 100 y number (%) y number (%) y number (%) *** on on *** *** 0 *** *** *** *** 0 *** 0 *** *** *** on on 0 2.5 5 10 20 40 0 2.5 5 10 20 40 0 2.5 5 10 20 40 Col Azelastine (μM) Col Azelastine (μM) Azelastine (μM) 50 *** *** Col HT29 DLD1 HCT116 *** *** 0 HT29 DLD1 Soft agar col Azelastine (mg/kg) C D 0 10 20 200μm 200μm 200μm 28 Azelastine (0 mg/kg) Liver (g) Azelastine (10 mg/kg) 50μm 50μm 50μm t 26 Azelastine (20 mg/kg) 24 y weigh y 22 od B 20 200μm 200μm 200μm 2 4 6 8 10 12 14 16 18 20 Time (day) Kidney 50μm 50μm 50μm H & E 200μm 200μm 200μm Lung 50μm 50μm 50μm Figure S1 A B Power Law Global Error Model Normal Q−Q Plot slope = 1 16 intercept = −1.4 1 0.02 14 0.04 0 0.06 7 0.09 −1 12 0.0 0.08 In (sd) −2 0.05 0.03 10 Residuals 0.01 −3 adj. r 2 = 0.989 8 Pearson = 0.82 −4 10 12 14 16 18 −3 −2 −1 0 1 2 3 ln(mean) Standard Normal C Residuals vs. rank D Histogram of residuals 80 4 60 2 2e�05 4e�05 8e 0.00014 1e�04 6e�05 �05 0.00016 2e�04 0 0.00018 40 6e�05 8e�05 1e�04 0.00012 Counts Residuals 4e�05 2e�05 20 −4 −2 0 0 500 1000 1500 2000 2500 −4 −2 0 2 4 Rank of mean Residuals Figure S2 HT29 DLD1 Azelastine (μM) 0 20 40 0 20 40 Bcl-XL 1.0 0.9 0.7 1.0 0.9 0.6 Bax 1.0 1.6 1.7 1.0 3.6 4.3 Bcl-2 1.0 1.0 0.7 1.0 0.9 0.6 Actin Figure S3 15 A HT29 DLD1 HT29 ** Mitochondria DAPI Merge Mitochondria DAPI Merge 10 * 0 5 10μm 10μm M) Network mitochondria (%) 0 μ 0 10 20 e ( e Azelastine (μM) in 10 20 DLD1 10μm 10μm 15 * * Azelast 10 20 5 10μm 10μm Network mitochondria (%) 0 0 10 20 B C HT29 DLD1 HCT116 D Azelastine (μM) con MEK con MEK con MEK Azelastine HCT116 ty ili 1.5 HCT116 (μM) 0 20 40 MEK ) * ab p-ERK 1.0 1.5 1.0 1.5 1.0 1.5 vi ll 1.0 1.0 0.7 0.2 p-ERK hange ce c e d ERK 1.0 2.2 1.0 1.5 1.0 1.5 l iv 0.5 fo ( 1.0 1.0 1.0 ERK at 1.0 1.1 Actin 1.0 1.1 1.0 0.9 Rel 0.0 Actin 0 40 0 40 MEK _ _ + + E 8 HT29 ns HT29 DLD1 6 ns Mitochondria DAPI Merge Mitochondria DAPI Merge 4 0 2 Network mitochondria (%) 10μm 10μm 0 0 10 20 M) μ Azelastine (μM) e ( e MEK in 10 st MEK 15 DLD1 10μm 10μm ns ns Azela 10 20 10μm 10μm 5 Network mitochondria (%) F G 0 150 HT29 150 DLD1 0 10 20 Azelastine (μM) ns ns ty HCT116 ns ty ns MEK ili ili MEK ab 100 100 Azelastine ab vi (μM) 0 10 20 vi ll ll Drp1 ce control) ce control) f f e 1.0 0.9 0.9 e iv 50 50 iv p-Drp1 at at (% o 1.0 1.1 1.1 (% o Rel Actin Rel 0 0 0 20 40 0 20 40 0 20 40 0 20 40 Azelastine (μM) Rotenone (μM) Azelastine (μM) Rotenone (μM) Figure S4 A B HT29 HCT116 HT29 HCT116 150 Azelastine (μM) 150 Azelastine (μM) 0 0 10 10 100 20 20 sgcon sgHRH1#1sgHRH1#2sgcon sgHRH1#1sgHRH1#2 100 * * * * * * * HRH1 ** * * * 1.0 0.0 0.0 1.0 0.0 0.0 50 ** 50 % ofcontrol) % ofcontrol) （ （ Relative cell viability cell Relative Actin viability cell Relative 0 0 sgcon sgcon C sgHRH1#1 sgHRH1#2 sgHRH1#1 sgHRH1#2 H2O PK DIA PK HT29 Azelastine PK PK DIA Azelastine D HT29 DLD1 sgconsgARF1#1sgconsgARF1#2 sgconsgARF1#1sgconsgARF1#2 ARF1 1.0 0.0 1.0 0.0 1.0 0.0 1.0 0.0 Actin HT29 DLD1 E Azelastine (μM) Azelastine (μM) 150 * * * 0 150 * 0 * 20 * 20 * 40 * 40 100 100 50 50 (% of control) (% (% of control) (% Relative cell viability cell Relative Relative cell viability cell Relative 0 0 sgcon sgcon sgARF1#1 sgARF1#2 sgARF1#1 sgARF1#2 HT29 DLD1 Azelastine (μM) F 150 Azelastine (μM) 150 0 0 ** 20 ** 20 100 100 50 50 (% of control) (% (% of control) (% Relative cell viability cell Relative Relative cell viability cell Relative 0 0 __ _ _ Mdivi-1 (μM) + + Mdivi-1 (μM) + + Figure S5 A B C ) 200 con HCT116 RKO ity 200 con il ARF1 * ARF1 * 150 * 150 HCT116 con ARF1 con ARF1 * 100 100 ARF1 RKO 1.0 2.4 1.0 4.0 50 50 (% ofcontrol) Actin Colony number (% 0 Relative cellRelative viab 0 con ARF1 HCT116 RKO HCT116 RKO D E F con ARF1 ARF1+U0126 HCT116 RKO HCT116 con 200 ARF1 *** con ARF1 ARF1+U0126con ARF1 ARF1+U0126 150 ** RKO ARF1 100 1.0 2.3 3.0 1.0 2.1 1.7 ) ) 50 p-ERK HCT116 RKO 1.0 10.0 1.5 200 150 0 1.0 5.1 1.2 * * HCT116 RKO ERK 150 Soft agar colony number (%) 100 100 1.0 1.0 1.2 1.0 1.0 1.5 50 Actin 50 0 0 Colony number (% Colony number (% con con G H ARF1 ARF1 con HCT116 ity RKO ity il ARF1 il 200 250 ARF1+U0126 ARF1+U0126 200 ARF1+U0126 * 150 * 200 ** ** 150 150 100 100 50 50 100 0 (% ofcontrol) 0 (% ofcontrol) con 50 con cellRelative viab Relative cellRelative viab ARF1 ARF1 0 Soft agar colony number (%) ARF1+U0126 HCT116 RKO ARF1+U0126 J HT29 DLD1 I 150 150 ity ity -Dox il il -Dox ** *** +Dox +Dox *** shcon shARF1#1shARF1#2shcon shARF1#1shARF1#2 100 *** 100 Dox - + - + - + - + - + - + ARF1 50 50 (% of control) (% 1.0 1.3 0.9 0.2 1.3 0.4 1.0 0.9 1.0 0.5 0.7 0.4 of control) (% Relative cell viab cell Relative Actin viab cell Relative 0 0 HT29 DLD1 shcon shcon K L shARF1#1shARF1#2 shARF1#1shARF1#2 150 HT29 -Dox * +Dox ** HT29 DLD1 25 HT29 100 ** Mitochondria DAPI Merge Mitochondria DAPI Merge 20 50 15 * 10 0 sicon 10μm 10μm 5 Soft agar colony number (%) shcon
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