The Potential of PIP3 in Enhancing Wound Healing

Abstract

Given the role of phosphatidylinositol 3,4,5-trisphosphate (PIP3) in modulating cellular processes such as proliferation, survival, and migration, we hypothesized its potential as a novel therapeutic agent for wound closure enhancement. In this study, PIP3 was examined in its free form or as a complex with cationic starch (Q-starch) as a carrier. The intracellular bioactivity and localization of free PIP3 and the Q-starch/PIP3 complexes were examined. Our results present the capability of Q-starch to form complexes with PIP3, facilitate its cellular membrane internalization, and activate intracellular paths leading to enhanced wound healing. Both free PIP3 and Q-starch/PIP3 complexes enhanced monolayer gap closure in scratch assays and induced amplified collagen production within HaCAT and BJ fibroblast cells. Western blot presented enhanced AKT activation by free or complexed PIP3 in BJ fibroblasts in which endogenous PIP3 production was pharmacologically inhibited. Furthermore, both free PIP3 and Q-starch/PIP3 complexes expedited wound closure in mice, after single or daily dermal injections into the wound margins. Free PIP3 and the Q-starch/PIP3 complexes inherently activated the AKT signaling pathway, which is responsible for crucial wound healing processes such as migration; this was also observed in wound assays in mice. PIP3 was identified as a promising molecule for enhancing wound healing, and its ability to circumvent PI3K inhibition suggests possible implications for chronic wound healing.

Selective Termination of Autophagy-Dependent Cancers

“…PIP2 biosynthesis is essential for autophagy and for the biosynthesis of PIP3 by the action of PIK3C/PI3K isozymes (Figure 1C). PIP3 is concentrated on the plasma membrane where it activates an array of regulatory proteins through the AKT signaling pathway to promote cell growth, proliferation, differentiation, migration and survival [43,82]. Thus, perturbations in PIP3 levels affect cellular homeostasis in both normal and cancer cells, which accounts for the fact that PIK3C/PI3K inhibitors induced a wide variety of toxic effects during clinical trials in cancer therapy [83].…”

“…Similarly, deletion of the Fab1/PIKFYVE gene in yeast impairs nuclear division, resulting in aneuploid and binucleate cells [95]. Cytotoxicity requires excessive cytoplasmic vacuolation and AKT suppression [96,97], suggesting that cell death results from inhibition of both PIP2 and PIP3 biosynthesis [82].…”