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Supporting Information Yang et al. 10.1073/pnas.1603244113 A Cell line = BJeLR cells ALOX5 ALOX12 ALOX12B Ct = N.D. Ct = N.D. Ct = 34.434 ALOX15 ALOX15B ALOXE3 Ct = 30.711 Ct = 34.132 Ct = 28.326 Cell line = HT-1080 cells ALOX5 ALOX12 ALOX12B Ct = N.D. Ct = N.D. Ct = 35.46 ALOX15 ALOX15B ALOXE3 Ct = N.D. Ct = 34.64 Ct = 31.137 B Cell line = HT-1080 cells 1.5 1.5 1.0 1.0 0.5 0.5 ALOX15B mRNA level ALOX15B expression) (relative ALOX15B mRNA level ALOX15B expression) (relative 0.0 0.0 siNeg siNeg siALOX15B siALOXE3 Fig. S1. (A) Expression analysis of ALOX genes in BJeLR and HT-1080 cells. The figures show the amplification plot of each ALOX isoform. Triplicate samples were analyzed for each gene using mRNA preparation from BJeLR cells. The red lines in each plot indicate ACTB gene amplification that served as endogenous control in the quantification. The gene name and the Ct number, if was possible to determine, are presented. A Ct value greater than 35 is considered a weak expression level, which suggests that ALOXE3 is the major isoform expressed in these cell lines. N.D., not determined. (B) Knockdown of ALOX15B and ALOXE3 expression by the pool of siRNAs was confirmed using qPCR analysis. Data are presented as mean ± SD; n = 3. Yang et al. www.pnas.org/cgi/content/short/1603244113 1of3 GFP-ALOX5 location n.s. BJeHBJeH BJeHLTBJeHLT BJeLRBJeLR 50 40 DMSO 30 20 10 0 Translocated cells per field cells Translocated (IONO group) BJeH BJeLR BJeHLT [IONO], 113 μM [IONO], BJeHBJeH BJeHLTBJeHLT BJeLRBJeLR Ferroptosis Ferroptosis Resistant Sensitive Fig. S2. GFP-ALOX5 translocated to the perinuclear membrane region upon ionomycin and erastin treatment. GPF-ALOX5 remained within the nucleus when expressed in BJeH, BJeHLT, and BJeLR cells (Upper) but translocated to the perinuclear membrane region upon ionomycin treatment (Lower). Unlike erastin- induced translocation (Fig. 3G), all three BJ cells responded equally to the ionomycin treatment. BJ cells were treated with 113 μM ionomycin for 12 h. Bar graph, n = 3–4; n.s., not significant. (Scale bars, 60 μm.) Fig. S3. There is a possible link between PHKG2 and cellular iron involving tumor suppressor p53. PHKG2 gene and biomolecules associated with cellular iron were put into a single network space in Ingenuity Pathway Analysis (IPA) software. The “grow” function of IPA software was used to expand the number of edges in the network space, and then the “connect” function was used to identify possible connections among the molecules. This revealed p53 as a hy- pothetical link between PHKG2 and cellular iron. Yang et al. www.pnas.org/cgi/content/short/1603244113 2of3 Other Supporting Information Files Dataset S1 (XLSX) Yang et al. www.pnas.org/cgi/content/short/1603244113 3of3.

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