Thematic Minireview Series on Phospholipase D and Cancer

Abstract

Phospholipase D (PLD) signaling plays a critical role in cell growth and proliferation, vesicular trafficking, secretion, and endocytosis. At the cellular level, PLD and its reaction product, phosphatidate, interact with a large number of protein partners that are directly related to the actin cytoskeleton and cell migration. Cancer invasion and metastasis rely heavily on cellular motility, and as such, they have put PLD at center stage in cancer research. This minireview series highlights some of the molecular mechanisms that provide evidence for the emerging tumorigenic potential of PLD, the role of the microenvironment, and putative connections with inflammation. PLD represents a potential target for the rational development of therapeutics against cancer and other diseases. PLD3 catalyzes the conversion of phosphatidylcholine to PA and choline. The enzyme reaction was first identified from carrots in 1947 by Hanahan and Chaikoff (1, 2), and indeed, most of the early work on the biochemistry of PLD was performed with the enzyme from plants (3). The existence of PLD in mammals was not discovered until 1973 (4). From the mid-1980s to the early 1990s, it became apparent that PLD played a major role in lipid signaling by generating PA, which was then converted to diacylglycerol for the activation of PKC (5). Interest in PLD intensified with the observations that PA itself governed several physiological processes that include cell growth and proliferation, vesicular trafficking, secretion, and endocytosis (6 -12).Studies on PLD were challenged with serious difficulties due to limited knowledge of its regulation on a molecular level, as well as the difficulty of purifying the enzyme from natural sources. However, the PLD field received a strong boost in 1994 when Wang et al. (13) identified the PLD gene from castor bean. This seminal contribution led to the identifications of orthologous genes from yeast (14) and mammals (15-17). The field also expanded when the action of PLD was implicated in Parkinson and Alzheimer diseases, as well as in several cancers.Apart from generating one of the major lipid second messengers, PA, PLD interacts with a large number of protein partners, some of which are directly related to the actin cytoskeleton, which is involved with the protein machinery responsible for cell adhesion and migration (18). Precisely for this role, certain pathologies that rely on cell migration, such as cancer metastasis, have put PLD at center stage in cancer research. High levels of PLD activity are reported in a variety of cancers, such as breast, gastric, colorectal, and lung (19 -22) cancers. Further, radiation in combination with PLD inhibition (specific for both PLD1 and PLD2) has been shown to be an efficient way to improve radiosensitivity of breast cancer cell lines and in animal models (23)(24)(25)(26).Recent studies with animal models have indicated that PLD is integral to breast cancer progression by increasing tumor growth and cell invasion (27-29). Significant expansion of the PLD field is e...

Comparative Network Analysis of Patients with Non-Small Cell Lung Cancer and Smokers for Representing Potential Therapeutic Targets

“…Intriguingly, mutations in ARFGEF1, an activator of ARF1, have been reported in lung cancer 100 . Among these three proteins, PLDs have been garnering attention as potential contributors to cellular signalling of tumours 101 . Surprisingly, PLD represented an important intersection for other pathways in this study, and the first super network was constructed based on this enzyme.…”

The Significant Role of the Microfilament System in Tumors

“…DMTN is a differentially transcriptional expressed gene; its downregulation regulates the actin cytoskeleton through Rac1 signal transduction and catalyzes the metastasis of colorectal cancer cells (69). The upregulation of plasminogen activator inhibitor 1 (PAI1) drives actin cytoskeleton rearrangement of triple negative breast cancer (TNBC) cells and increases migration (70). Cell adhesion molecules E-cadherin, phospholipase D (PLD), and various integrins regulate cell polarity, differentiation, proliferation, and migration through their close interactions with the actin cytoskeleton network (44,(71)(72)(73).…”

<p>Anti-Metastatic Effect of Gold Nanoparticle-Conjugated <em>Maclura tricuspidata</em> Extract on Human Hepatocellular Carcinoma Cells</p>

“…PLD is activated extensively by various oncogenes including v-Raf, v-Ras and v-Src, and hence, it is currently one of the major molecular targets for the treatment of several cancers including pancreatic, breast, lung, gastric, and liver cancers. 19 – 21 …”