Identification of lipid-phosphatidylserine (PS) as the target of unbiasedly selected cancer specific peptide-peptoid hybrid PPS1.
Phosphatidylserine (PS) is an anionic phospholipid maintained on the inner-leaflet of the cell membrane and is externalized in malignant cells. We previously launched a careful unbiased selection targeting biomolecules (e.g. protein, lipid or carbohydrate) distinct to cancer cells by exploiting HCC4017 lung cancer and HBEC30KT normal epithelial cells derived from the same patient, identifying HCC4017 specific peptide-peptoid hybrid PPS1. In this current study, we identified PS as the target of PPS1. We validated direct PPS1 binding to PS using ELISA-like assays, lipid dot blot and liposome based binding assays. In addition, PPS1 recognized other negatively charged and cancer specific lipids such as phosphatidic acid, phosphatidylinositol and phosphatidylglycerol. PPS1 did not bind to neutral lipids such as phosphatidylethanolamine found in cancer and phosphatidylcholine and sphingomyelin found in normal cells. Further we found that the dimeric version of PPS1 (PPS1D1) displayed strong cytotoxicity towards lung cancer cell lines that externalize PS, but not normal cells. PPS1D1 showed potent single agent anti-tumor activity and enhanced the efficacy of docetaxel in mice bearing H460 lung cancer xenografts. Since PS and anionic phospholipid externalization is common across many cancer types, PPS1 may be an alternative to overcome limitations of protein targeted agents.
Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX 77204, USA.
Tanvi J
TJ
Desai
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Jason E
JE
Toombs
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.|Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.|Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
John D
JD
Minna
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.|Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.|Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.|Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Rolf A
RA
Brekken
Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX 77204, USA.|Department of Cancer Systems Imaging, MD Anderson Cancer Center, Houston, TX 77030, USA.
Damith Gomika
DG
Udugamasooriya
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008563:Membrane Lipids / Q000037:antagonists & inhibitors / Q000378:metabolism; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry; D034444:Peptoids / Q000737:chemistry; D010718:Phosphatidylserines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D008563:Membrane Lipids; D009842:Oligopeptides; D010455:Peptides; D034444:Peptoids; D010718:Phosphatidylserines; C515192:Pieczenik peptide sequence 1
anti-cancer agents; lung cancer; non-protein biomarkers; peptoids; phosphatidylserine