NDLI: The PIKfyve-ArPIKfyve-Sac3 triad in human breast cancer: functional link between elevated Sac3 phosphatase and enhanced proliferation of triple negative cell lines

Content Provider	PubMed Central
Author	Ikonomov, Ognian C. Catherine, Filios Diego, Sbrissa Chen, Xuequn Assia, Shisheva
Copyright Year	2013
Abstract	The phosphoinositide 5-kinase PIKfyve and 5-phosphatase Sac3 are scaffolded by ArPIKfyve in the PIKfyve-ArPIKfyve-Sac3 (PAS) regulatory complex to trigger a unique loop of PtdIns3P – PtdIns(3,5)P2 synthesis and turnover. Whereas the metabolizing enzymes of the other 3-phosphoinositides have already been implicated in breast cancer, the role of the PAS proteins and the PtdIns3P – PtdIns(3,5)P2 conversion is unknown. To begin elucidating their role, in this study we monitored the endogenous levels of the PAS complex proteins in cell lines derived from hormone-receptor positive (MCF7 and T47D) or triple-negative breast cancers (TNBC) (BT20, BT549 and MDA-MB-231) as well as in MCF10A cells derived from non-tumorigenic mastectomy. We report profound upregulation of Sac3 and ArPIKfyve in the triple-negative vs. hormone sensitive breast cancer or non-tumorigenic cells, with BT cell lines showing the highest levels. siRNA-mediated knockdown of Sac3, but not that of PIKfyve, significantly inhibited proliferation of BT20 and BT549 cells. In these cells, knockdown of ArPIKfyve had only a minor effect, consistent with a primary role for Sac3 in TNBC cell proliferation. Intriguingly, steady-state levels of PtdIns(3,5)P2 in BT20 and T47D cells were similar despite the 6-fold difference in Sac3 levels between these cell lines. Rather, steady-state levels of PtdIns3P and PtdIns5P, both regulated by the PAS complex, were significantly reduced in BT20 cells vs. T47D or MCF10A cell lines, consistent with elevated Sac3 affecting directly or indirectly the homeostasis of these lipids in TNBC. Together, our results uncover an unexpected role for Sac3 phosphatase in TNBC cell proliferation. Database analyses, discussed herein, reinforce the involvement of Sac3 in breast cancer pathogenesis.
Related Links	http://dx.doi.org/10.1016/j.bbrc.2013.09.080
Ending Page	347
Page Count	6
Starting Page	342
File Format	PDF
ISSN	0006291X
e-ISSN	10902104
Journal	Biochemical and biophysical research communications
Issue Number	2
Volume Number	440
Language	English
Publisher Date	2013-10-01
Access Restriction	Open
Subject Keyword	Biophysics Cell Biology Biochemistry Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Molecular Biology Biochemistry Biophysics

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PIKfyve-ArPIKfyve-Sac3 Core Complex

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