Role of cellular small molecule IP6K1 in cancer progression
10 Jul 2016
Dr Rashna Bhandari, Senior Fellow,
Centre for DNA Fingerprinting and Diagnostics, Hyderabad
Inositol pyrophosphate (IP7) is one among the many small molecules in living cells that govern important cellular functions and is present in all eukaryotic organisms, from yeast to humans. Structurally, IP7 is a six carbon ring (inositol /cyclohexane hexanol) attached to 5 mono-phosphates and one di-phosphate (I=inositol; P7=seven phosphates). In mice and humans, IP7 is synthesized from IP6 by IP6 kinases (IP6Ks). Three isoforms of IP6Ks are found in mammals, and gene deletion of each isoform leads 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 tumuorigenesis. 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 an oral carcinogen.
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 cells lacking IP6K1, revealing a role for this protein in the interaction of the cell surface with extracellular proteins. We initiated a collaboration with India Alliance Senior Fellow, Dr Nagaraj Balasubramanian at IISER, Pune, who is an expert in the study of cell adhesion dependent signalling. Together, we determined that cells lacking IP6K1 manifest defects in cell shape or cytoskeleton remodeling triggered by their adhesion to extracellular proteins, leading to reduced cell spreading and migration. Expression of active, but not inactive IP6K1, reversed migration defects in IP6K1 knockout cells, suggesting that IP7 synthesis by IP6K1 promotes cell locomotion. Cytoskeleton remodeling and cell migration support the ability of cancer cells to achieve their complete oncogenic potential. Human cancer cells with lower IP6K1 levels displayed reduced migration and invasion into the extracellular matrix. When fed an oral carcinogen, mice lacking IP6K1 showed reduced susceptibility 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 required to support 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.
Deletion of inositol hexakisphosphate kinase 1 (IP6K1) reduces cell migration and invasion, conferring protection from aerodigestive tract carcinoma in mice. Rathan S. Jadava, Dharmika Kumara, Natasha Buwac, Shubhra Gangulia, Sitalakshmi R. Thampattya, Nagaraj Balasubramanian, Rashna Bhandari. Cellular Signalling (April 2016).
Banner image : Credit Benita Denny, Wellcome Images
Abnormal cell - artworkArtwork illustrating a single rogue cell amongst its normal neighbours. This could be the beginnings of a cancerous growth.