eIF5A-PEAK1 signaling regulates KRAS protein expression.

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eIF5A-PEAK1 signaling regulates KRAS protein expression. eIF5A-PEAK1 signaling regulates KRAS protein expression. A, eIF5A-PEAK1 regulates KRas protein expression. The indicated cancer cells stably expressing lentiviruses encoding control shRNA (−) or shRNA to eIF5A (sh-eIF5A) were Western blotted for the indicated proteins. P-Erk1/2, phosphorylated activated Erk 1 and 2 kinases. +, relative dependency on KRas for cell growth. +/−, moderate dependency on KRas for cell growth. −, independent of KRas for cell growth. B, Syngeneic orthotopic tumor growth of PDA4964 cells in B6/129 mice expressing control or eIF5A shRNA (sh5A). Tumors were resected at 2 weeks, weighed, and Western blotted for the indicated proteins as in A. C, The indicated cells were treated with 20 μmol/L GC7 for 48 hours and then Western blotted for the indicated proteins. 5A-hyp, hypusinated/activated form of eIF5A. D, The 779E human PDAC subcutaneous tumors were allowed to grow for 10 days in nude mice, then treated with vehicle (Ctrl, PBS, n = 7) or GC7 (25 mg/kg daily, n = 8). Tumor volume was measured with a digital caliper. E, Tumors from D were excised and Western blotted for the indicated proteins. F, The indicated PDAC cells were treated with siRNA to KRas or control siRNAs (−) and Western blotted for the indicated proteins. G, The indicated PDAC cells were infected with a lentivirus encoding eIF5A and Western blotted for the indicated proteins. H, siRNA-mediated KRas knockdown in 779E cells treated as in G and examined for colony growth in vitro and Western blotted for the indicated proteins. Results are relative to control siRNA cells. Inset, picture of colonies stained with crystal violet. I, The 779E cells stably expressing lentiviruses encoding PEAK1 or control vectors and Western blotted for the indicated proteins. J, siRNA-mediated KRas knockdown in 779E cells treated as in I and examined for colony growth in vitro and Western blotted for the indicated proteins. K, The 779E cells were induced to express eIF5A, PEAK1, or both eIF5A and PEAK1, and examined for cell growth in vitro. Results are relative to control cells transfected with empty vectors. *, P < 0.05; **, P < 0.01, Student t test. Ken Fujimura et al. Cancer Res 2018;78:1444-1456 ©2018 by American Association for Cancer Research