Deletion of inositol hexakisphosphate kinase 1 (IP6K1) reduces cell migration and invasion, conferring protection from aerodigestive tract carcinoma in mice

Abstract

Inositol hexakisphosphate kinases (IP6Ks), a family of enzymes found in all eukaryotes, are responsible for the synthesis of 5-diphosphoinositol pentakisphosphate (5-IP7) from inositol hexakisphosphate (IP6). Three isoforms of IP6Ks are found in mammals, and gene deletions of each isoform lead to diverse, non-overlapping phenotypes in mice. Previous studies show a facilitatory role for IP6K2 in cell migration and invasion, properties that are essential for the early stages of tumorigenesis. However, IP6K2 also has an essential role in cancer cell apoptosis, and mice lacking this protein are more susceptible to the development of aerodigestive tract carcinoma upon treatment with the oral carcinogen 4-nitroquinoline-1-oxide (4NQO). Not much is known about the functions of the equally abundant and ubiquitously expressed IP6K1 isoform in cell migration, invasion and cancer progression. We conducted a gene expression analysis on mouse embryonic fibroblasts (MEFs) lacking IP6K1, revealing a role for this protein in cell receptor-extracellular matrix interactions that regulate actin cytoskeleton dynamics. Consequently, cells lacking IP6K1 manifest defects in adhesion-dependent signaling, evident by lower FAK and Paxillin activation, leading to reduced cell spreading and migration. Expression of active, but not inactive IP6K1 reverses migration defects in IP6K1 knockout MEFs, suggesting that 5-IP7 synthesis by IP6K1 promotes cell locomotion. Actin cytoskeleton remodeling and cell migration support the ability of cancer cells to achieve their complete oncogenic potential. Cancer cells with lower IP6K1 levels display reduced migration, invasion, and anchorage-independent growth. When fed an oral carcinogen, mice lacking IP6K1 show reduced progression from epithelial dysplasia to invasive carcinoma. Thus, our data reveal that like IP6K2, IP6K1 is also involved in early cytoskeleton remodeling events during cancer progression. However, unlike IP6K2, IP6K1 is essential for 4NQO-induced invasive carcinoma. Our study therefore uncovers similarities and differences in the roles of IP6K1 and IP6K2 in cancer progression, and we propose that an isoform-specific IP6K1 inhibitor may provide a novel route to suppress carcinogenesis.

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

“…Deletion of Ip6k1 significantly influences various aspects of mouse biology, and thus, targeting this isoform is expected to be beneficial in obesity, T2D (45,58,69,70), innate immunity (59), thromboembolism (71), cancer metastasis (56), and psychiatric and neurodegenerative diseases (49). Ip6k1 KO mice are protected against high-fat diet-induced (HFD-induced) weight gain, insulin resistance, and fatty liver (58).…”

“…Accordingly, IP6Ks exhibit distinct cellular functions (45,54). IP6K1-generated 5-IP7 modulates cell metabolism, signaling, exocytosis, and migration (48,(55)(56)(57)(58). IP6K1-generated 5-IP7 regulates insulin signaling by inhibiting the insulin-sensitizing protein kinase Akt both in vivo and in vitro (58)(59)(60)(61), whereas it promotes insulin secretion from pancreatic β cells (57).…”

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.…”

“…Recent work from our laboratory showed that IP6K1 also promotes cell migration and invasion. 108 Knockdown of IP6K1 expression in cancer cells leads to a reduction in cell migration, invasion and anchorage-independent growth. Ip6k1 knockout mice fed with the oral carcinogen 4NQO showed reduced progression from epithelial dysplasia to invasive carcinoma in the upper aerodigestive tract as compared with their wildtype littermates, showing that IP6K1 is also required to promote cell invasion in vivo.…”

Targeting the Inositol Pyrophosphate Biosynthetic Enzymes in Metabolic Diseases

“…Amplification or constitutive hyperactivation (~10-50-fold) [239,240] of Akt causes tumorigenesis in vivo [241], whereas no tumors are formed when these conditions are not met [241]. Notably, a 2-3-fold increase in Akt activation improves metabolic functions [12,22] without forming tumors [242] in Ip6k1-KO mice. Moreover, Ip6k1-KO mice are protected from tumorigenesis and metastasis [242].…”