Inositol pyrophosphates promote tumor growth and metastasis by antagonizing liver kinase B1

Abstract

The inositol pyrophosphates, molecular messengers containing an energetic pyrophosphate bond, impact a wide range of biologic processes. They are generated primarily by a family of three inositol hexakisphosphate kinases (IP6Ks), the principal product of which is diphosphoinositol pentakisphosphate (IP7). We report that IP6K2, via IP7 synthesis, is a major mediator of cancer cell migration and tumor metastasis in cell culture and in intact mice. IP6K2 acts by enhancing cell-matrix adhesion and decreasing cell-cell adhesion. This action is mediated by IP7-elicited nuclear sequestration and inactivation of the tumor suppressor liver kinase B1 (LKB1). Accordingly, inhibitors of IP6K2 offer promise in cancer therapy.I nositol pyrophosphates, conserved eukaryotic messenger molecules with a pyrophosphate bond, mediate numerous physiologic processes including regulation of Akt (1), insulin secretion (2), ATP production (3), DNA repair (4), and damage response (5). Exemplified by diphosphoinositol pentakisphosphate (PPIP5, IP7), inositol pyrophosphates are primarily generated by a family of three inositol hexakisphosphate (IP6) kinases (IP6K) (6, 7) and also may be formed by a more recently described group of IP6/7 kinases (8). IP6K1 and IP6K2 are widely distributed, whereas IP6K3 is expressed primarily in the brain (9). A related enzyme, inositol polyphosphate multikinase (IPMK), converts IP3 to IP4 and IP5, displays physiologic PI3 kinase activity (10), and noncatalytically acts as a transcriptional coactivator (11) and stabilizer of the mTOR complex-1 (12). Whether IP6Ks and IPMK play direct roles in tumor progression remains unexplored.Tumor cell metastasis requires loss of cell-cell adhesion and gain of migratory and invasive properties, a collective program known as epithelial-mesenchymal transition (EMT), which is also critical for embryonic development (13). Cell-cell adhesion and cell migration/invasion are primarily driven by E-cadherinmediated cell clustering (14) and focal-adhesion-based cellmatrix interactions (15), respectively. Whether these two distinct adhesion processes are concurrently or independently regulated remains poorly understood.The tumor suppressor LKB1 has been separately reported to inhibit FAK activation (16) and to enhance E-cadherin expression (17)(18)(19). LKB1 is mutated in Peutz-Jeghers syndrome patients who tend to develop cancer at multiple sites (20). As a master kinase controlling the activity of AMPK and 13 other AMPK-like kinases (21), LKB1 mediates diverse cellular processes such as polarity, adhesion, metabolism, tumor growth/metastasis, and neuronal axon initiation/branching (22). Unlike conventional protein kinases, LKB1 is not activated by activation loop phosphorylation but by protein-protein interaction with two other subunits of the heterotrimeric holoenzyme: STRAD and Mo25. LKB1 can also exist as an inactive nuclear monomer. STRAD binds and stabilizes LKB1 (23) in the cytosol, where it is phosphorylated at serine 428 by PKCζ (24). Whether cytosolic localization enhance...

Inositol hexakisphosphate (IP6) generated by IP5K mediates cullin-COP9 signalosome interactions and CRL function

“…This antagonism between upstream and downstream kinases of IP6 metabolism is also found in regulating the tumor suppressor LKB1. Catalytic activity of IPMK activates LKB1 (43), whereas that of IP6K2 suppresses it (44). IP6 plays structural roles in a number of important cellular (23).…”

Adipocyte-specific deletion of Ip6k1 reduces diet-induced obesity by enhancing AMPK-mediated thermogenesis

“…5-IP7 may also indirectly inhibit AMPK. For example, 5-IP7 promotes nuclear localization of LKB1 in cancer cells, which diminishes its activity toward the cytosolic targets (80). Cytosolic LKB1 phosphorylates AMPK (81).…”

Inositol Pyrophosphates: Energetic, Omnipresent and Versatile Signalling Molecules

“…Recent studies have shed light on the role of IP 7 in the promotion of tumour growth and metastasis using in vitro and in vivo approaches. 107,108 The Snyder group showed that gene deletion of Ip6k2 in HCT116 human colorectal cancer cells and Ip6k2 knockdown in breast and lung cancer cell lines led to a reduction in focal adhesion kinase (FAK) phosphorylation, correlating with reduced cell spreading and cell-matrix adhesion. 107 Epithelial to mesenchymal transition properties including cell migration and invasion were also significantly reduced in these cells.…”

“…107,108 The Snyder group showed that gene deletion of Ip6k2 in HCT116 human colorectal cancer cells and Ip6k2 knockdown in breast and lung cancer cell lines led to a reduction in focal adhesion kinase (FAK) phosphorylation, correlating with reduced cell spreading and cell-matrix adhesion. 107 Epithelial to mesenchymal transition properties including cell migration and invasion were also significantly reduced in these cells. Subcutaneous xenograft of Ip6k2 knockout HCT116 cells in immune-compromised mice led to tumours that were smaller in size as compared with those formed by parent HCT116 cells.…”