The H1047R point mutation in p110 alpha changes the morphology of human colon HCT116 cancer cells

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.

The metastasis suppressor protein NM23-H1 modulates the PI3K-AKT axis through interaction with the p110α catalytic subunit

“…The NM23-H1 interactome also extends to proteins directly involved in actin remodeling with a key role in regulation of cell motility 24 , 30 . Furthermore, an increased number of filopodia in Human colon cancer cells HCT116 positive for the p110α gain of function point mutation H1047R has been previously described 9 . The analysis of the structures associated with cell motility provides an important clues as regards to the dynamic processes associated with actin remodeling in the context of cell migration 38 .…”

“…5C and S 5A ). Importantly, silencing of p110α led to a significant reduction in migrated cells of greater than 2.5-fold, which is likely due to the role of the p110α kinase in PI3K signaling and promotion of cell invasion 9 , 27 (Figs. 5D and S 5B ).…”

“…In particular, protruding structures of the plasmalemma known as Filopodia are fundamental to cellular processes which include migration, invasion, adhesion, angiogenesis, and cell–cell contact 29 . Contextually, it is also known that a specific p110α gain of function point mutation H1047R is responsible for an increased number of Filopodia production, change in cell shape and an increase in metastatic activity 9 . Moreover, we previously showed evidence of direct interaction between NM23-H1 and the small GTPase of the Rho-subfamily Cdc42 30 , a key regulator of different cell functions including cell morphology, migration, endocytosis, and cell cycle progression, and an important role in formation of the extension and maintenance of the actin-rich surface projections filopodia 30 .…”

“…Indeed, gain of function mutations of the p110α gene ( PI3KCA ) occurs in up to one-third of human colorectal cancers (CRCs). The most frequent p110α cancer-specific gain of function mutation is the H1047R mutation and is responsible for increased migration, filopodia formation, and significant changes in cell morphology 9 . Notably, Qian et al have shown that activation of PI3K alone is sufficient to remodel actin filaments and increase cell migration through the activation of protein kinase B (PKB) or Akt 10 .…”

Treatment response to idelalisib in a patient with immunodeficiency-associated Burkitt lymphoma harboring a PIK3CA H1047R mutation

“…In addition, we identified two mutations in the catalytic alpha subunit of the PIK3CA gene, i.e., p.H1047R (variant allele frequency (VAF) 5.0%) and p.Q1033R (VAF 3.7%) affecting exon 21 on the same allele. This PIK3CA H1047R mutation affects the highly conserved catalytic subunit p110a and has previously been identified at high frequency in many types of solid tumors [ 9 , 10 ]. In patients receiving PI3K/AKT/mTOR inhibitors, the presence of the PIK3CA H1047R mutation was associated with improved response rates compared with patients with wild-type PIK3CA or other PIK3CA mutations (38% vs. 10% vs. 13%) [ 11 ].…”