Phospholipase D Meets Wnt Signaling: A New Target for Cancer Therapy

Kang, Dong Woo; Choi, Kang Yell; Min, Do Sik

doi:10.1158/0008-5472.can-10-2463

Cited by 61 publications

(41 citation statements)

References 35 publications

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“…Overexpression of PLD has been reported to protect cancer cells from apoptosis, 37 and aberrant activation/expression of PLD has been widely implicated in a variety of cancers. 18,19 PLD1 inhibition led to a great increase in the level of LC3-II protein in a variety of cells, and PA suppressed starvationinduced autophagy, suggesting that PLD activity has a negative role in autophagy. To assess whether LC3-II formation is altered by perturbation, one can assess its level in the presence of Baf A1, which inhibits LC3-II degradation by blocking autophagosome-lysosome fusion.…”

Section: Discussionmentioning

confidence: 99%

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Phospholipase D-mediated autophagic regulation is a potential target for cancer therapy

2013

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Autophagy is a catabolic process in which cell components are degraded to maintain cellular homeostasis by nutrient limitations. Defects of autophagy are involved in numerous diseases, including cancer. Here, we demonstrate a new role of phospholipase D (PLD) as a regulator of autophagy. PLD inhibition enhances autophagic flux via ATG1 (ULK1), ATG5 and ATG7, which are essential autophagy gene products critical for autophagosome formation. Moreover, PLD suppresses autophagy by differentially modulating phosphorylation of ULK1 mediated by mTOR and adenosine monophosphate-activated protein kinase (AMPK), and by suppressing the interaction of Beclin 1 with vacuolar-sorting protein 34 (Vps34), indicating that PLD coordinates major players of the autophagic pathway, AMPK-mTOR-ULK1 and Vps34/Beclin 1. Ultimately, PLD inhibition significantly sensitized in vitro and in vivo cancer regression via genetic and pharmacological inhibition of autophagy, providing rationale for a new therapeutic approach to enhancing the anticancer efficacy of PLD inhibition. Collectively, we show a novel role for PLD in the molecular machinery regulating autophagy.

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Section: Discussionmentioning

confidence: 99%

“…18,19 Despite the implications of PLD and autophagy in cancer-related processes, current evidence linking these two fields of research is severely limited.…”

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confidence: 99%

Phospholipase D-mediated autophagic regulation is a potential target for cancer therapy

2013

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“…Fli-1 genes are members of the erythroblast transformation-specific (ETS) family of transcription factors. Overexpression of EWS-Fli or Fli increases expression of PLD2 (60). PLD2, which is mainly involved in the increased PLD activity in EWS tumors (59), is a novel target of EWS-Fli-1 as well as Fli-1 transcription factor on the ETS binding site that functions as the principal promoter of the PLD2 gene.…”

Section: Ewing Sarcoma Fusion Protein Ews-fli and Fli Selectively Imentioning

confidence: 99%

“…Recently, both PLD1 and PLD2 were identified as target genes of Wnt/␤-catenin signaling via binding of TCF4/␤-catenin in their promoters (21,22,60). ␤-Catenin and TCF4 were shown to elevate expression and activity of PLD isozymes, whereas PLD isozymes were found to act as a positive feedback regulator of Wnt signaling, which subsequently promotes Wnt-driven anchorage-independent growth of colorectal cancer cells (Fig.…”

Section: Wnt/␤-catenin Signaling Up-regulates Expression Of Both Pld1mentioning

confidence: 99%

Functional Regulation of Phospholipase D Expression in Cancer and Inflammation

Kang

Choi

Min

2014

Journal of Biological Chemistry

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Phospholipase D (PLD) regulates downstream effectors by generating phosphatidic acid. Growing links of dysregulation of PLD to human disease have spurred interest in therapeutics that target its function. Aberrant PLD expression has been identified in multiple facets of complex pathological states, including cancer and inflammatory diseases. Thus, it is important to understand how the signaling network of PLD expression is regulated and contributes to progression of these diseases. Interestingly, small molecule PLD inhibitors can suppress PLD expression as well as enzymatic activity of PLD and have been shown to be effective in pathological mice models, suggesting the potential for use of PLD inhibitors as therapeutics against cancer and inflammation. Here, we summarize recent scientific developments regarding the regulation of PLD expression and its role in cancer and inflammatory processes.Phospholipase D produces phosphatidic acid (PA) 2 via hydrolysis of phospholipids such as phosphatidylcholine and cardiolipin. As a lipid second messenger, PA has been implicated in a wide range of pathophysiological processes including proliferation, oncogenesis, inflammation, phagocytosis, membrane fusion, and spermatogenesis. Phosphatidylcholine-specific PLD1 and PLD2 are the classic mammalian isoforms of PLD (1, 2). Growth factor, mitogen, and inflammatory cytokines up-regulate expression and activity of PLD; however, aberrant dysregulation of PLD occurs in various cancers and inflammation-related diseases. Accordingly, it is important to understand how expression of PLD is regulated and contributes to these diseases.An association between inflammation and cancer has been observed (3) and supported by recent epidemiological data that indicated ϳ20% of cancer deaths are linked to chronic infections and persistent inflammation (4). The PLD signaling pathway provides a possible molecular link between inflammation and cancer; however, systematic investigation of PLD as a therapeutic target has only begun within the last few years with the development of small molecule PLD inhibitors and PLD knock-out mice (5-13). This review covers recent advances in the regulation of PLD expression and its role in cancer and inflammation.

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“…Thus, the PLD-PA-Rac pathway plays an important role in the metastasis of cancer cells, and might provide a connection for integrin and PLD-mediated cancer metastasis [167]. A new mechanism has also been suggested for PLD and PA mediated carcinogenesis through Wnt/ -catenin signaling network [168].…”

Section: Phospholipase Dmentioning

confidence: 99%