d-3-Deoxy-dioctanoylphosphatidylinositol induces cytotoxicity in human MCF-7 breast cancer cells via a mechanism that involves downregulation of the D-type cyclin-retinoblastoma pathway.
Phosphatidylinositol analogs (PIAs) were originally designed to bind competitively to the Akt PH domain and prevent membrane translocation and activation. d-3-Deoxy-dioctanoylphosphatidylinositol (d-3-deoxy-diC8PI), but not compounds with altered inositol stereochemistry (e.g., l-3-deoxy-diC8PI and l-3,5-dideoxy-diC8PI), is cytotoxic. However, high resolution NMR field cycling relaxometry shows that both cytotoxic and non-toxic PIAs bind to the Akt1 PH domain at the site occupied by the cytotoxic alkylphospholipid perifosine. This suggests that another mechanism for cytotoxicity must account for the difference in efficacy of the synthetic short-chain PIAs. In MCF-7 breast cancer cells, with little constitutively active Akt, d-3-deoxy-diC8PI (but not l-compounds) decreases viability concomitant with increased cleavage of PARP and caspase 9, indicative of apoptosis. d-3-Deoxy-diC8PI also induces a decrease in endogenous levels of cyclins D1 and D3 and blocks downstream retinoblastoma protein phosphorylation. siRNA-mediated depletion of cyclin D1, but not cyclin D3, reduces MCF-7 cell proliferation. Thus, growth arrest and cytotoxicity induced by the soluble d-3-deoxy-diC8PI occur by a mechanism that involves downregulation of the D-type cyclin-pRb pathway independent of its interaction with Akt. This ability to downregulate D-type cyclins contributes, at least in part, to the anti-proliferative activity of d-3-deoxy-diC8PI and may be a common feature of other cytotoxic phospholipids.
Department of Chemistry, Boston College, 2609 Beacon Street, Chestnut Hill, MA 02467, USA. Electronic address: cstrelko@gmail.com.
Cheryl S
CS
Gradziel
Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT 06520, USA. Electronic address: pajordan@ucsd.edu.
Peter A
PA
Jordan
Department of Chemistry, Boston College, 2609 Beacon Street, Chestnut Hill, MA 02467, USA. Electronic address: delilah.jewel@gmail.com.
Delilah
D
Jewel
Department of Biology, Higgins Hall, 140 Commonwealth Avenue, Boston College, Chestnut Hill, MA, USA. Electronic address: faydufort@gmail.com.
Fay J
FJ
Dufort
Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT 06520, USA. Electronic address: scott.miller@yale.edu.
Scott J
SJ
Miller
Department of Biology, Higgins Hall, 140 Commonwealth Avenue, Boston College, Chestnut Hill, MA, USA. Electronic address: chilest@bc.edu.
Thomas C
TC
Chiles
Department of Chemistry, Boston College, 2609 Beacon Street, Chestnut Hill, MA 02467, USA. Electronic address: mary.roberts@bc.edu.
Mary F
MF
Roberts
D001943:Breast Neoplasms / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D009682:Magnetic Resonance Spectroscopy; D010712:Phosphatidic Acids / Q000737:chemistry / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D000070539:Pleckstrin Homology Domains; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C000620191:3-deoxy-dioctanoylphosphatidylinositol; C530104:CCND1 protein, human; D010712:Phosphatidic Acids; D010716:Phosphatidylinositols; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; C084527:dioctanoylphosphatidic acid; D019938:Cyclin D1; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases
3-Deoxy-phosphatidylinositol; D-type cyclin-retinoblastoma protein pathway; Field-cycling NMR relaxometry; MCF-7 cells