Recent advances in understanding the molecular role of phosphoinositide-specific phospholipase C gamma 1 as an emerging onco-driver and novel therapeutic target in human carcinogenesis

Abstract

Phosphoinositide metabolism is crucial intracellular signaling system that regulates a plethora of biological functions including mitogenesis, cell proliferation and division. Phospholipase C gamma 1 (PLCγ1) which belongs to phosphoinositide-specific phospholipase C (PLC) family, is activated by many extracellular stimuli including hormones, neurotransmitters, growth factors and modulates several cellular and physiological functions necessary for tumorigenesis such as cell survival, migration, invasion and angiogenesis by generating inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) via hydrolysis of phosphatidylinositol 4,5-biphosphate (PIP2). Cancer remains as a leading cause of global mortality and aberrant expression and regulation of PLCγ1 is linked to a plethora of deadly human cancers including carcinomas of the breast, lung, pancreas, stomach, prostate and ovary. Although PLCγ1 cross-talks with many onco-drivers and signaling circuits including PI3K, AKT, HIF1-α and RAF/MEK/ERK cascade, its precise role in carcinogenesis is not completely understood. This review comprehensively discussed the status quo of this ubiquitously expressed phospholipase as a tumor driver and highlighted its significance as a novel therapeutic target in cancer. Furthermore, we have highlighted the significance of somatic driver mutations in PLCG1 gene and molecular roles of PLCγ1 in several major human cancers, a knowledgebase that can be utilized to develop novel, isoform-specific small molecule inhibitors of PLCγ1.

Keywords: Cancer therapeutics; Growth factor receptor; Molecular oncology; Phosphoinositide signaling pathways; Phospholipase Cγ1; Receptor tyrosine kinases.