title: Inhibition of p85, the non-catalytic subunit of phosphatidylinositol 3-kinase, exerts potent antitumor activity in human breast cancer cells.
abstract: The phosphoinositide 3-kinases (PI3Ks) are heterodimers consisting of the catalytic subunit p110 and the regulatory subunit p85. The PI3K/Akt pathway is strongly deregulated in breast cancer (BC) representing one of the mechanisms of resistance to therapies. Therefore, the identification of inhibitors of PI3K components represents one of the main goals to produce therapeutic agents. Here, we evaluated the efficacy of a phosphopeptide 1257 (P-1257) that targeting p85 strongly inhibits PI3K activity. We tested the effects of P-1257 administration in vitro and in vivo using BC cells expressing different levels of ErbB-2 and resistant or responsive to Trastuzumab. We demonstrated that inhibition of p85 activity by P-1257 induces cell death and sensitizes JIMT-1 and KPL-4 ErbB-2-overexpressing BC cells to Trastuzumab treatment. It is noteworthy that P-1257 delivery in vivo by electroporation or liposomes significantly inhibits the proliferation of tumor cells engrafted at subcutaneous and visceral sites. Overall, our data indicate that the p85 subunit is a valid target for therapeutic approaches and suggest that the structure of the peptide used in our study could be utilized for the development of novel drugs to apply in combination with therapies that fail to cure BCs with high PI3K activity.
authors.affiliation: Department of Experimental Oncology, Regina National Elena Cancer Institute, Via delle Messi d'Oro 156, Rome, Italy. folgiero@ifo.it
authors.forename: V
authors.initials: V
authors.lastname: Folgiero
authors.forename: S E
authors.initials: SE
authors.lastname: Di Carlo
authors.forename: G
authors.initials: G
authors.lastname: Bon
authors.forename: E P
authors.initials: EP
authors.lastname: Spugnini
authors.forename: A
authors.initials: A
authors.lastname: Di Benedetto
authors.forename: S
authors.initials: S
authors.lastname: Germoni
authors.forename: M
authors.initials: M
authors.lastname: Pia Gentileschi
authors.forename: A
authors.initials: A
authors.lastname: Accardo
authors.forename: M
authors.initials: M
authors.lastname: Milella
authors.forename: G
authors.initials: G
authors.lastname: Morelli
authors.forename: G
authors.initials: G
authors.lastname: Bossi
authors.forename: M
authors.initials: M
authors.lastname: Mottolese
authors.forename: R
authors.initials: R
authors.lastname: Falcioni
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D020134:Catalytic Domain; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010748:Phosphopeptides / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D055504:Insulin Receptor Substrate Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010748:Phosphopeptides; D051057:Proto-Oncogene Proteins c-akt; D020893:Receptor, ErbB-3; C526292:IRS1 protein, human