Physiological function of phospholipase D2 in anti-tumor immunity: regulation of CD8+ T lymphocyte proliferation

Abstract

Two major phospholipase D (PLD) isozymes in mammals, PLD1 and PLD2, hydrolyze the membrane phospholipid phosphatidylcholine to choline and the lipid messenger phosphatidic acid. Although their roles in cancer cells have been well studied, their functions in tumor microenvironment have not yet been clarified. Here, we demonstrate that PLD2 in cytotoxic CD8+ T cells plays a crucial role in anti-tumor immunity by regulating their cell proliferation. We found that growth of tumors formed by subcutaneously transplanted cancer cells is enhanced in Pld2-knockout mice. Interestingly, this phenotype was found to be at least in part attributable to the ablation of Pld2 from bone marrow cells. The number of CD8+ T cells, which induce cancer cell death, significantly decreased in the tumor produced in Pld2-knockout mice. In addition, CD3/CD28-stimulated proliferation of primary cultured splenic CD8+ T cells is markedly suppressed by Pld2 ablation. Finally, CD3/CD28-dependent activation of Erk1/2 and Ras is inhibited in Pld2-deleted CD8+ T cells. Collectively, these results indicate that PLD2 in CD8+ T cells plays a key role in their proliferation through activation of the Ras/Erk signaling pathway, thereby regulating anti-tumor immunity.

Phospholipase D2 is a positive regulator of sirtuin 1 and modulates p53-mediated apoptosis via sirtuin 1

“…Here, we show that PLD2, but not PLD1, contains the LXXLL motif in the PX domain and acts as a positive regulator of SIRT1. PLD2 mediates mitogenic signaling from growth factors and regulates receptor-induced cell survival 13,[30][31][32][33] .…”

Effect of simulated microgravity on metabolism of HGC‑27 gastric cancer cells

“…MT1-MMP, tethered to the plasma membrane, is a key protein associated with the migration of cancer cells (67). PLD2 generates small lipid molecules, such as phosphatidic acid, which can regulate the movement of the cytoskeleton, proliferation and migration (68)(69)(70). Therefore, it has been suggested that PLD2 and its small lipid molecules can regulate MT1-MMP for invasion and metastasis.…”