DAG/PKCδ and IP3/Ca2+/CaMK IIβ Operate in Parallel to Each Other in PLCγ1-Driven Cell Proliferation and Migration of Human Gastric Adenocarcinoma Cells, through Akt/mTOR/S6 Pathway

Abstract

Phosphoinositide specific phospholipase Cγ (PLCγ) activates diacylglycerol (DAG)/protein kinase C (PKC) and inositol 1,4,5-trisphosphate (IP3)/Ca2+/calmodulin-dependent protein kinase II (CaMK II) axes to regulate import events in some cancer cells, including gastric adenocarcinoma cells. However, whether DAG/PKCδ and IP3/Ca2+/CaMK IIβ axes are simultaneously involved in PLCγ1-driven cell proliferation and migration of human gastric adenocarcinoma cells and the underlying mechanism are not elucidated. Here, we investigated the role of DAG/PKCδ or CaMK IIβ in PLCγ1-driven cell proliferation and migration of human gastric adenocarcinoma cells, using the BGC-823 cell line. The results indicated that the inhibition of PKCδ and CaMK IIβ could block cell proliferation and migration of BGC-823 cells as well as the effect of inhibiting PLCγ1, including the decrease of cell viability, the increase of apoptotic index, the down-regulation of matrix metalloproteinase (MMP) 9 expression level, and the decrease of cell migration rate. Both DAG/PKCδ and CaMK IIβ triggered protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/S6 pathway to regulate protein synthesis. The data indicate that DAG/PKCδ and IP3/Ca2+/CaMK IIβ operate in parallel to each other in PLCγ1-driven cell proliferation and migration of human gastric adenocarcinoma cells through Akt/mTOR/S6 pathway, with important implication for validating PLCγ1 as a molecular biomarker in early gastric cancer diagnosis and disease surveillance.

Comprehensive review of targeted therapy for colorectal cancer

“…[63][64][65][66][67] IP3 and DAG promote the release of intracellular Ca 2+ and activate protein kinase C to promote carcinogenesis. 68,69 Moreover, recent studies stated that the SH3 domain of PLC-γ1 might be of great importance in the interaction with EGFR. EGF mediates PLC-γ1 binding to AKT, altering its activity through the SH3 domain.…”

Downregulation of type 3 inositol (1,4,5)-trisphosphate receptor decreases breast cancer cell migration through an oscillatory Ca2+ signal

“…Ca 2+ increases can occur in the form of waves, spikes or oscillations with various impact on cell migration progression [ 7 ]. Several plasma membrane channels that increase Ca 2+ into the cytosol, such as the transient receptor potential (TRP) channels [ 8 ] and Orai/STIM channels [ 9 , 10 ] have been described in cancer cell migration, but implication of inositol-(1,4,5)-trisphosphate (IP 3 ) receptors (IP 3 Rs) [ 11 ] and ryanodine receptors (RyRs) [ 12 ] in such process remain fragmented.…”

Phosphoinositide-specific phospholipase Cγ1 inhibition induces autophagy in human colon cancer and hepatocellular carcinoma cells

“…Phosphoinositide-specific phospholipase C (PLC) γ1 is activated by both receptor and non-receptor tyrosine kinases and can induce hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) to generate two second messengers, inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG), which trigger a series of signalling pathways to regulate cellular processes 13 – 17 . For instance, depletion of PLCγ expression or inhibition of its activity not only increases cisplatin-induced apoptosis but also suppresses the invasive ability of RhoGDI2-overexpressing SNU-484 gastric cancer cells 15 .…”