Crosstalk Of Pim And Lkb1 Kinases In Driving Growth Of Prostate Cancer Cells.

Abstract The oncogenic PIM kinases and the tumor-suppressive LKB1 kinase have been linked to regulation of cell growth and proliferation. Here we have investigated their potential interactions as well as their relative impacts on tumorigenic growth of prostate cancer cells. The cellular functions of PIM and LKB1 kinases were evaluated using either pan-PIM inhibitors or CRISPR/Cas9-based genomic editing, with which all three PIM family members and/or LKB1 were knocked out from PC3 prostate cancer cells. In addition to cell-based 2D proliferation assays, we examined tumor growth using the chick embryo chorioallantoic membrane (CAM) xenograft model. In this report, we show that inhibition of PIM expression or activity results in increased phosphorylation of AMPK at Thr172 in an LKB1-dependent fashion. With in vitro kinase assays, we demonstrate that LKB1 is a novel direct substrate for PIM kinases and that Ser334 is one of the PIM target sites in LKB1. Accordingly, wild-type LKB1, but not the phosphodeficient S334A mutant can restore PIM inhibitor-induced AMPK phosphorylation in LKB1 knock-out cells. Whereas loss of LKB1 exaggerates formation of PC3-based tumors in the CAM xenograft model, co-deletion of PIM kinases attenuates it. The impairment of cell proliferation and tumor growth in cells lacking both PIM and LKB1 kinases not only underscores the potential crosstalk in signaling between these kinases, but also suggest that PIM inhibitors could be used to restrain growth of LKB1-deficient tumors. Citation Format: Kwan Long Mung, William Eccleshall, Niina M. Santio, Adolfo Rivero-Müller, Cecilia Sahlgren, Päivi J. Koskinen. Crosstalk of PIM and LKB1 kinases in driving growth of prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 79.