Increased phospholipase D activity contributes to tumorigenesis in prostate cancer cell models
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Increased phospholipase D activity contributes to tumorigenesis in prostate cancer cell models Mathieu Borel1 · Olivier Cuvillier2 · David Magne1 · Saida Mebarek1 · Leyre Brizuela1 Received: 22 December 2019 / Accepted: 4 July 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Prostate cancer (PCa) is the most frequent cancer among men and the first cause of death over 65. Approximately 90% of patients with advanced disease will develop bone metastasis, which dramatically reduces long-term survival. Therefore, effective therapies need to be developed, especially when disease is still well-localized. Phospholipase D (PLD), an enzyme that hydrolyzes phosphatidylcholine to yield phosphatidic acid, regulates several cellular functions as proliferation, survival, migration or vesicular trafficking. PLD is implicated in numerous diseases such as neurodegenerative, cardiovascular, autoimmune disorders or cancer. Indeed, PLD controls different aspects of oncogenesis including tumor progression and resistance to targeted therapies such as radiotherapy. PLD1 and PLD2 are the only isoforms with catalytic activity involved in cancer. Surprisingly, studies deciphering the role of PLD in the pathophysiology of PCa are scarce. Here we describe the correlation between PLD activity and PLD1 and PLD2 expression in PCa bone metastasis-derived cell lines C4-2B and PC-3. Next, by using PLD pharmacological inhibitors and RNA interference strategy, we validate the implication of PLD1 and PLD2 in cell viability, clonogenicity and proliferation of C4-2B and PC-3 cells and in migration capacity of PC-3 cells. Last, we show an increase in PLD activity as well as PLD2 protein expression during controlled starvation of PC-3 cells, concomitant with an augmentation of its migration capacity. Specifically, upregulation of PLD activity appears to be PKC-independent. Taken together, our results indicate that PLD, and in particular PLD2, could be considered as a potential therapeutic target for the treatment of PCa-derived bone metastasis. Keywords Phospholipase D · Prostate cancer · Migration · Controlled starvation
Introduction Prostate cancer (PCa) is the fourth main cancer in both sexes and the second most common cancer in males [1]. Approximately 90% of patients with advanced disease will develop bone metastasis in the form of osteoblastic lesions [2]. Currently, the number of patients with metastatic PCa
Saida Mebarek and Leyre Brizuela have contributed equally to the work. * Leyre Brizuela leyre.brizuela‑madrid@univ‑lyon1.fr 1
Univ Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5246, ICBMS, 69622 Lyon, France
Université de Toulouse, UPS, CNRS UMR 5089, Institut de Pharmacologie et de Biologie Structurale, IPBS, 31077 Toulouse Cedex, France
2
is increasing, probably leading to even higher death rates in the upcoming years [3]. Phospholipase D (PLD) catalyzes the hydrolysis of phosphatidylcholine (PC) into phosphatidic acid (PA) and choline [4]. PLD has been implicated in a variety of patho
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