Thematic series on phospholipase D and cancer

Cover of the JBC thematic minireview series on Phospholipase D and cancer
A new thematic minireview series in the Journal of Biological Chemistry focuses on phospholipase D and its role in cancer. PLD signaling controls a variety of cellular activities (namely, proliferation, migration and lipid metabolism) and thus plays a key role in cancer invasion and metastasis. The series highlights PLD’s tumorigenic potential, tools to study its in-vivo function, its putative role in inflammatory diseases, and regulation of levels of the signaling metabolite, phosphatidic acid. A deeper understanding of PLD has broad applications in developing targeted drug therapies for cancer.
In the first article, Julian Gomez–Cambronero briefly describes the various mammalian isoforms of PLD and discusses mechanisms by which PLD1 and PLD2 affect cell migration, cell adhesion and proliferation. In light of these activities, PLD has a direct impact on cancer growth, invasion and metastasis and is therefore a therapeutic target in cancer treatments. The author points out recent developments in PLD research and their implications in cancer treatments. For example, combining radiation with PLD-inhibitor drugs is an effective strategy to treat chemotherapy-resistant and radiation-resistant cancer cells. The author concludes by specifying the challenges remaining in PLD research, such as defining the in-vivo mechanisms of PLD signaling and establishing the crystal structure of PLD.
Yi Zhang and Michael Frohman in the second minireview discuss the tools used to study the physiological role of PLD1 within a tumor and its microenvironment. The authors describe how small molecular inhibitors and cell lines were used to define PLD’s function and PLD1’s role in cancer. However, these in-vitro approaches suffer from limited physiological relevance. Alternatively, studies using animal models (particularly PLD1-deficient mice) provide better insight into the in-vivo role of PLD1 in cell metabolism, tumorigenesis, angiogenesis, autophagic response and therapy resistance. The authors also mention new techniques, such as genetically encoded phosphatidic acid sensors and advanced intravital imaging, that can elucidate the impact of PLD1 in early steps of tumor development and metastasis.
Dong Woo Kang and colleagues focus on regulation of PLD expression and its implications in cancer and inflammation in the third minireview. Cancerous phenotypes and inflammatory diseases are characterized by aberrant PLD expression. In this article, the authors elaborate on the dysregulation of PLD expression and activity in cancer, the use of PLD-selective inhibitors and microRNA for cancer therapeutics, amplification of PLD expression resulting from genomic alterations in PLD gene and dynamic control of PLD signaling by transcription factors in cancer. The authors also discuss PLD regulation in various inflammatory conditions and the mechanisms by which PLD-selective inhibitors, such as triptolide and rebamipide, exert antitumorigenic and anti-inflammatory effects. The authors emphasize that PLD-selective inhibitors have great therapeutic potential for treating cancers and inflammatory conditions.
In the fourth and final minireview, David Foster and colleagues highlight the intracellular regulation of phosphatidic acid and its implication in cancer-cell survival via mammalian/mechanistic target of rapamycin, or mTOR, activity. The ability of mTOR to integrate nutrients and growth-factor signals during cell-cycle progression depends heavily on intracellular phosphatidic acid levels. Phosphatidic acid is a signaling metabolite produced by three major metabolic sources: enzymatic action of PLD on phosphatidylcholine, the diacylglycerol kinase pathway and the lysophosphatidic acid acyl transferase pathway. The authors discuss how compensatory pathways maintain intracellular levels of phosphatidic acid when one pathway is compromised. Given mTOR’s dependency on phosphatidic acid and strong mTOR activity in cancer cells, the authors suggest that interfering with phosphatidic acid metabolism could prove to be an effective therapeutic strategy for cancer treatments.
In the introductory commentary for the collection, series organizers Gomez–Cambronero and George M. Carman remark that, despite the evident advances in PLD research, many issues need further investigation. Realizing the full potential of PLD inhibition in cancer therapeutics requires a better understanding of various PLD isoforms, their role during cancer progression and the evaluation of isoform-specific PLD inhibitors in clinical trials.
Indumathi SridharanIndumathi Sridharan ( earned her bachelor’s degree in bioinformatics in India. She holds a Ph.D. in molecular biochemistry from Illinois Institute of Technology, Chicago.
She did her postdoctoral work in bionanotechnology at Northwestern University.