Abstract
The class IA phosphatidylinositol 3-kinases (PI3K) is involved in controlling changes in cell morphology, which is a highly coordinated cellular event. This event is powered by actin filament polymerization and remodeling. The gain-of-function mutations in the catalytic subunit of p110α of class IA PI3K, which occur in up to one-third of human colorectal cancers (CRCs), are capable of causing dysregulation of cell signaling and thus may result in the alteration in cell morphology and motility and in turn cause cancer metastasis. In vivo studies have demonstrated that cell lines bearing the H1047R point mutation, the most frequent cancer-specific mutation in the kinase domain of p110α, are more metastatic than cells carrying wild-type p110α. In the current study, we show that the H1047R in p110α of PI3K decreases F-actin polymerization, increases the formation of filopodia and significantly changes the cell morphology in HCT116 cancer cells. The anti-apoptotic protein B-cell lymphoma 2 (Bcl-2), which is also involved in actin polymerization and cell migration, is downregulated by the H1047R mutation in p110α. Our data suggest that the H1047R mutation in PI3K is responsible for the rearrangement of the cytoskeleton, alteration in cell morphology and enhancing cell motility, and that Bcl-2 may be involved in the H1047R mutation-mediated morphological changes and increased migratory capability.
Highlights
The dysregulation of the phosphoinositide 3-kinase (PI3K) signaling pathway has been implicated in the progression and metastasis of human cancers, including colorectal cancers (CRCs), and can frequently be induced by genetic mutations in class IAPI3K
Our results indicate that the H1047R mutation in PI3K decreases F-actin polymerization, while significantly increasing cellular filopodia formation and cell motility, as compared with WT PI3K
To investigate the effect of the H1047R mutation on cell morphology and actin cytoskeleton structure, we used cell lines harboring either WT or mutant (MUT; H1047R) p110α of PI3K, which were generated by asymmetric deletion of the PIK3CA allele from the CRC parental cell line HCT116
Summary
The dysregulation of the phosphoinositide 3-kinase (PI3K) signaling pathway has been implicated in the progression and metastasis of human cancers, including colorectal cancers (CRCs), and can frequently be induced by genetic mutations in class IA. Patients carrying a PIK3CA mutation have a higher rate of disease relapse than patients lacking p110α mutations.[8] it has been reported that these mutations cause a gain of enzymatic fun,[3,4] which in terms of cancer cell survival, may depend on the type of p110α mutations.[5,6] These cancerspecific mutations in class IA PI3Ks are located in two specific ‘hotspot’ regions: in the helical domain or in the kinase domain of the p110α catalytic subunit These ‘hotspot’ mutations have been identified in CRCs and account for 80% of p110α-bearing mutations.[2] The most frequent mutation in the p110α kinase domain is at position 1047 where histidine is frequently substituted with arginine (H1047R).[1]. Our data suggest that B-cell lymphoma 2 (Bcl-2) may be involved in the H1047R mutationmediated cell morphological changes and increased cell migration
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