title: 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.
authors.affiliation: Laboratory of Cell Signalling, Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500001, India; Graduate Studies, Manipal University, Manipal, India.
authors.forename: Rathan S
authors.initials: RS
authors.lastname: Jadav
authors.affiliation: Laboratory of Cell Signalling, Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500001, India.
authors.forename: Dharmika
authors.initials: D
authors.lastname: Kumar
authors.affiliation: Department of Biology, Indian Institute of Science Education and Research, Pune 411008, India.
authors.forename: Natasha
authors.initials: N
authors.lastname: Buwa
authors.affiliation: Laboratory of Cell Signalling, Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500001, India; Graduate Studies, Manipal University, Manipal, India.
authors.forename: Shubhra
authors.initials: S
authors.lastname: Ganguli
authors.affiliation: Laboratory of Cell Signalling, Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500001, India; Graduate Studies, Manipal University, Manipal, India.
authors.forename: Sitalakshmi R
authors.initials: SR
authors.lastname: Thampatty
authors.affiliation: Department of Biology, Indian Institute of Science Education and Research, Pune 411008, India.
authors.forename: Nagaraj
authors.initials: N
authors.lastname: Balasubramanian
authors.affiliation: Laboratory of Cell Signalling, Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500001, India. Electronic address: rashna@cdfd.org.in.
authors.forename: Rashna
authors.initials: R
authors.lastname: Bhandari
mesh_terms: D015112:4-Nitroquinoline-1-oxide; D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement / Q000235:genetics; D005110:Extracellular Space / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D006258:Head and Neck Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D006801:Humans; D007295:Inositol Phosphates / Q000494:pharmacology; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D015363:Quinolones; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C120195:4-nitroquinolone-1-oxide; D005353:Fibronectins; D007295:Inositol Phosphates; D015363:Quinolones; D034741:RNA, Small Interfering; D015112:4-Nitroquinoline-1-oxide; D017856:Phosphotransferases (Phosphate Group Acceptor); C099438:inositol hexakisphosphate kinase
keywords: Aerodigestive tract carcinoma; Cell invasion; Cell migration; Gene expression; Inositol hexakisphosphate kinase; Inositol pyrophosphate