A phospholipase D and protein kinase C inhibitor blocks the spreading of murine mammary adenocarcinoma cells altering f-actin and β1-integrin point contact distribution

Ghiso, Julio A. Aguirre; Farías, Eduardo; Alonso, Daniel F.; Arregui, Carlos; Joffé, Elisa Bal de Kier

doi:10.1002/(sici)1097-0215(19970529)71:5<881::aid-ijc29>3.0.co;2-9

Cited by 22 publications

(7 citation statements)

References 25 publications

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“…PLD has been implicated in human cancer progression 9–13 , as well as reorganization of the actin cytoskeleton and cell motility 31 . As such, PLD may be an unappreciated molecular target whose inhibition could block tumor cell invasion 32–34 .…”

Section: Resultsmentioning

confidence: 99%

“…PLD activity also regulates mTOR, a serine/ threonine kinase responsible for triggering cell survival pathways 39,40 . In addition to participating in cell survival pathways, PLD is thought to contribute to cancer metastasis via multiple mechanisms, including cytoskeletal rearrangement and cell migration 31 . Recent reports suggest PLD may also contribute to metastasis through the induction of matrix metalloproteinase (MMP) secretion and extracellular matrix degradation 41–45 .…”

Section: Discussionmentioning

confidence: 99%

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Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness

et al. 2009

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Phospholipase D (PLD) is an essential enzyme responsible for the production of the lipid second messenger phosphatidic acid. Phosphatidic acid participates in both G protein-coupled receptor and receptor tyrosine kinase signal transduction networks. The lack of potent and isoform-selective inhibitors has limited progress in defining the cellular roles of PLD. We used a diversity-oriented synthetic approach and developed a library of PLD inhibitors with considerable pharmacological characterization. Here we report the rigorous evaluation of that library, which contains highly potent inhibitors, including the first isoform-selective PLD inhibitors. Specific members of this series inhibit isoforms with > 100-fold selectivity both in vitro and in cells. A subset of inhibitors was shown to block invasiveness in metastatic breast cancer models. These findings demonstrate the power of diversity-oriented synthesis combined with biochemical assays and mass spectrometric lipid profiling of cellular responses to develop the first isoform-selective PLD inhibitors—a new class of antimetastatic agents.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness

et al. 2009

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“…It will be beneficial for a normal cell to have a controlling mechanism to shut down or slow down the production of PA, a pleiotropic second messenger with potentially harmful effects to the cell if unchecked. We know that inhibition of PLD-derived PA production inhibits migration of adenocarcinoma cells (1,8). In this line of reasoning, we present here for the first time three phosphorylation-incapable mutants that can be an index of a new PLD2 regulatory mechanism.…”

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confidence: 75%

A Comprehensive Model That Explains the Regulation of Phospholipase D2 Activity by Phosphorylation-Dephosphorylation

Henkels

Peng

Frondorf

et al. 2010

Molecular and Cellular Biology

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We report here that the enzymatic activity of phospholipase D2 (PLD2) is regulated by phosphorylationdephosphorylation. Phosphatase treatment of PLD2-overexpressing cells showed a biphasic nature of changes in activity that indicated the existence of "activator" and "inhibitory" sites. We identified three kinases capable of phosphorylating PLD2 in vitro-epidermal growth factor receptor (EGFR), JAK3, and Src (with JAK3 reported for the first time in this study)-that phosphorylate an inhibitory, an activator, and an ambivalent (one that can yield either effect) site, respectively. Mass spectrometry analyses indicated the target of each of these kinases as Phospholipase D2 (PLD) catalyzes the hydrolysis of phosphatidylcholine to generate the lipid second messenger phosphatidic acid (PA) and choline. There are two mammalian isoforms: PLD1 (20) and PLD2 (12, 33). They share a highly conserved "HKD" domain necessary for catalysis (39). PLD has been implicated in a variety of physiological cellular functions, such as intracellular protein trafficking, cytoskeletal dynamics, membrane remodeling, and cell proliferation in mammalian cells and meiotic division and sporulation in yeast (6,15,16,32,42). PLD regulation in cells falls into two major signaling categories. One is by the small GTPase proteins Arf and Rho (3,5,11,43), and the other is by growth factors/ mitogens such as epidermal growth factor (EGF), plateletderived growth factor, insulin, and serum that implicate tyrosine kinases (2,12,21,22,34). Several gaps in knowledge of the second arm remain in spite of its importance in cell signaling. The isoform PLD1 can be phosphorylated on tyrosine, but this does not lead to changes in activity (35, 36).The isoform PLD2, which is expressed as a constitutively active enzyme in many cell types (47), can be detected as a phosphotyrosine protein both in vivo (25) and in vitro (17,25,41). PLD2 overexpression induces the transformation of cells (27,34,37,48), and the activation of this enzyme enhances cellular processes favorable for the metastasis of EL4 lymphoma cells (30). PLD also activates STAT3 by interacting with the thyroid oncogenic kinase RET/PTC (29). PLD2 can form a complex with the EGF receptor (EGFR) (12, 46) or with Pyk2 and Src kinases (4). Hydrogen peroxide and EGF induce PLD phosphorylation and PKC-␣ activation (38), while activation of PLD by 8-Br-cAMP is accomplished through Src, Ras, and ERK (49).Although all of these studies agree with respect to the presence of tyrosine kinases in PLD signaling, different conclusions were drawn regarding lipase activity. For example, whereas coexpression of PLD2 and Fyn or Fgr kinases lead to an enhancement of PLD activation and degranulation of mast cells (10), Ho et al. (23) , and Y 470 are important for PLD2 function (10) but, nevertheless, the overexpression of the phosphorylation-deficient mutant, PLD2-Y11F, increases PLD2 activity in resting or EGFactivated cells (12).Closely related to the enhancing effect of phosphorylationdeficient mutants, a new line of rese...

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“…A pivotal role in cell motility correlated to tumour invasion is played by cytoskeleton rearrangement, a physiologically important phenomenon that can be dysregulated provoking the activation and spreading of metastasis [160]. In this regard, PLD has been shown to induce reorganization of actin cytoskeleton [161,162] and cell motility [161]. Also Rho family GTPases, which directly activate PLD1 [163], have been demonstrated to modulate cell motility, thus suggesting a role for GTPases and PLD1 itself in the spread of metastasis [117].…”

Section: Tumour Invasionmentioning

confidence: 99%

Phospholipase D Inhibition: Beneficial and Harmful Consequences for a Double-Dealer Enzyme

Auricchio¹,

D'Aquilio²,

Chiurchiù³

et al. 2007

CEI

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One of the most promising strategies for drug design and development is the identification of new molecules able to selectively inhibit those enzymes involved in pathological processes, without affecting other enzymes associated with physiological functions. Nevertheless, some enzymes can show a double-edge aspect of their own inhibition, which can lead to positive as well as negative consequences according to the pathological state. Phospholipase D (PLD), an ubiquitous enzyme nowadays considered as a critical regulator of several aspects of cell biology and signal transduction pathways, is a clear example of those double-dealer enzymes. While a great deal has been learned about PLD structure, biological functions and activation/regulation mechanisms, little yet is known about the derivable effects of its potential negative regulation, also due to the lack of specific inhibitors. Multiple evidences on PLD involvement in many pathological states development and progression, including inflammation, carcinogenesis and metastases, have been supplied, so that a deregulation of its activity could contribute to attenuate or slow down the inflammatory and tumour formation/progression processes. On the other hand, in agreement with other previous observations, we have recently demonstrated the direct contribution of PLD activation in promoting intracellular mycobacterial killing. In this case, PLD inhibition resulted in a significant reduction of antimicrobial innate immune response and, hence, in a possible harmful effect. In the light of the above reported considerations, besides the recent advances in characterising new compounds able to selectively inhibit PLD activity and/or signalling, this review aimed at elucidating the potential dual beneficial/harmful consequences of PLD activity modulation.

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A phospholipase D and protein kinase C inhibitor blocks the spreading of murine mammary adenocarcinoma cells altering f-actin and β1-integrin point contact distribution

Cited by 22 publications

References 25 publications

Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness

Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness

A Comprehensive Model That Explains the Regulation of Phospholipase D2 Activity by Phosphorylation-Dephosphorylation

Phospholipase D Inhibition: Beneficial and Harmful Consequences for a Double-Dealer Enzyme

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