Abstract
BackgroundPhospholipases D1 and D2 (PLD1/2) are implicated in tumorigenesis through their generation of the signalling lipid phosphatidic acid and its downstream effects. Inhibition of PLD1 blocks prostate cell growth and colony formation. Here a role for PLD2 in prostate cancer (PCa), the major cancer of men in the western world, is examined.MethodsPLD2 expression was analysed by immunohistochemistry and western blotting. The effects of PLD2 inhibition on PCa cell viability and cell motility were measured using MTS, colony forming and wound-healing assays.ResultsPLD2 protein is expressed about equally in luminal and basal prostate epithelial cells. In cells from different Gleason-scored PCa tissue PLD2 protein expression is generally higher than in non-tumorigenic cells and increases in PCa tissue scored Gleason 6–8. PLD2 protein is detected in the cytosol and nucleus and had a punctate appearance. In BPH tissue stromal cells as well as basal and luminal cells express PLD2. PLD2 protein co-expresses with chromogranin A in castrate-resistant PCa tissue. PLD2 inhibition reduces PCa cell viability, colony forming ability and directional cell movement.ConclusionsPLD2 expression correlates with increasing Gleason score to GS8. PLD2 inhibition has the potential to reduce PCa progression.
Highlights
Phospholipases D1 and D2 (PLD1/2) are implicated in tumorigenesis through their generation of the signalling lipid phosphatidic acid and its downstream effects
PLD2 protein was detected in prostate cancer (PCa) cells cultured from several different Gleason-scored prostate tissue biopsies but expression varied between cell samples (Fig. 1c, d)
PLD2 protein expression was generally higher in PCa cells derived from Gleason-scored cancer biopsy samples than from a tissue sample defined as non-tumorigenic (Fig.1e)
Summary
Phospholipases D1 and D2 (PLD1/2) are implicated in tumorigenesis through their generation of the signalling lipid phosphatidic acid and its downstream effects. Many studies implicate phospholipase D (PLD) in tumorigenesis since total PLD activity and the expression of its two major isoforms PLD1 and PLD2 are elevated in many cancers where increases can correlate with prognosis.[1,2,3,4,5,6,7,8] Higher PLD activity is linked to survival and migration signals in human breast cancer cells and in androgen-insensitive prostate cancer cell lines.[9,10] Selective inhibition of PLD1 or PLD2 makes breast cancer cells more sensitive to radiation.[11] Investigations into the role of PLD in cancer have been aided by the development of new isoform-specific PLD1 and PLD2 inhibitors,[12,13,14] which reduce the proliferation of breast cancer cells in mice.[7,12,14]. The link between PLD and tumorigenesis is through phosphatidic acid (PtdOH), a product of PLD1 and PLD2 activity.[15,16] PtdOH is an intermediate in complex lipid synthesis[17] but it is a signalling lipid which, on formation, binds proteins at membrane surfaces leading to their activation.[13,18,19,20] The involvement of PtdOH in the recruitment and activation of mTOR (mammalian target of rapamycin), Raf and Akt/PKB kinase has defined a role for PLD in regulating cell survival, proliferation and tumorigenesis.[19,20,21] PtdOH formation inhibits protein phosphatase 1 and upregulates the NFκB and Wnt signalling pathways, further promoting both cancer cell survival and metastasis.[21,22,23]
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