Figure 5 from Nuclear Focal Adhesion Kinase Protects against Cisplatin Stress in Ovarian Carcinoma

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posted on 2024-12-20, 10:00 authored by Yichi Zhang, Marjaana Ojalill, Antonia Boyer, Xiao Lei Chen, Elise Tahon, Gaëtan Thivolle Lioux, Marvin Xia, Maryam Abbas, Halime Meryem Soylu, Douglas B. Flieder, Denise C. Connolly, Alfredo A. Molinolo, Michael T. McHale, Dwayne G. Stupack, David D. Schlaepfer

FAK nuclear localization supports KMF tumor cisplatin resistance in vivo with effects on downstream signaling. A, Experimental schematic: 7.5 million luciferase-expressing KMF FAK-WT or FAK-NLS⁻ cells were intraperitoneally injected into C57Bl6 mice (day 0), and IVIS luciferase imaging at day 5 was used to randomize experimental groups (n = 8 each). Mice were administered saline or cisplatin (CP, 4 mg/kg) and imaged on the indicated days. B, Graphical presentation of IVIS tumor burden from day 5 to day 31 as expressed as total flux in photons per second. Experimental groups are FAK-WT saline (green), FAK-WT plus CP (red), FAK-NLS⁻ saline (blue), and FAK-NLS⁻ + CP (violet). Values are means ± SD (n = 8, *, P < 0.05). C, Experimental schematic (similar as described in A) with decreased and more frequent cisplatin (2 mg/kg) administration over a longer experimental period. D, Representative IVIS images of CP-treated FAK-WT and FAK-NLS⁻ tumor-bearing mice on day 45. E, Graphical presentation of IVIS tumor burden from day 5 to day 45. Experimental groups are FAK-WT + CP (red) and FAK-NLS⁻ + CP (violet). Values are means ± SD (n = 8, **, P < 0.01). F, Enumeration (trypan blue–negative) of peritoneal cells recovered after euthanasia. Box and whisker plots show the mean (±SD, *, P < 0.05) for FAK-WT (red) and FAK-NLS⁻ (violet) tumor-bearing mice. G, Protein cell lysates were made from peritoneal collected cells from individual FAK-WT and FAK-NLS⁻ tumor-bearing mice (n = 5 each, M1 to M5) and immunoblotted for FAK, β-tubulin, active ERK (pERK), total ERK, active p38 (pp38), and total p38 MAPK. Immunoblotting for active JNK (pJNK) and total JNK were from the same samples but independent gels. H, Image quantitation of pERK to total ERK ratio from samples in G. Values are means ± SD (n = 5 experimental points, **, P < 0.01). FAK-WT values set to 1 (dotted line).

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ARTICLE ABSTRACT

FAK inhibitors are in combinatorial clinical testing with agents that prevent Ras–Raf–MAPK pathway activation in various cancers. This study suggests that nuclear FAK limits ERK/MAPK activation in supporting HGSOC cell survival to cisplatin stress. Overall, it is likely that targets of FAK-mediated survival signaling may be tumor type– and context-dependent.