title: Mechanistic Nanotherapeutic Approach Based on siRNA-Mediated DJ-1 Protein Suppression for Platinum-Resistant Ovarian Cancer.
abstract: We report an efficient therapeutic modality for platinum resistant ovarian cancer based on siRNA-mediated suppression of a multifunctional DJ-1 protein that is responsible for the proliferation, growth, invasion, oxidative stress, and overall survival of various cancers. The developed therapeutic strategy can work alone or in concert with a low dose of the first line chemotherapeutic agent cisplatin, to elicit a maximal therapeutic response. To achieve an efficient DJ-1 knockdown, we constructed the polypropylenimine dendrimer-based nanoplatform targeted to LHRH receptors overexpressed on ovarian cancer cells. The quantitative PCR and Western immunoblotting analysis revealed that the delivered DJ-1 siRNA downregulated the expression of targeted mRNA and corresponding protein by more than 80% in various ovarian cancer cells. It was further demonstrated that siRNA-mediated DJ-1 suppression dramatically impaired proliferation, viability, and migration of the employed ovarian cancer cells. Finally, the combinatorial approach led to the most pronounced therapeutic response in all the studied cell lines, outperforming both siRNA-mediated DJ-1 knockdown and cisplatin treatment alone. It is noteworthy that the platinum-resistant cancer cells (A2780/CDDP) with the highest basal level of DJ-1 protein are most susceptible to the developed therapy and this susceptibility declines with decreasing basal levels of DJ-1. Finally, we interrogate the molecular underpinnings of the DJ-1 knockdown effects in the treatment of the ovarian cancer cells. By using various experimental techniques, it was revealed that DJ-1 depletion (1) decreases the activity of the Akt pathway, thereby reducing cellular proliferation and migration and increasing the antiproliferative effect of cisplatin on ovarian cancer cells; (2) enhances the activity of p53 tumor suppressor protein therefore restoring cell cycle arrest functionality and upregulating the Bax-caspase pathway, triggering cell death; and (3) weakens the cellular defense mechanisms against inherited oxidative stress thereby increasing toxic intracellular radicals and amplifying the reactive oxygen species created by the administration of cisplatin.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University , Portland, Oregon 97201, United States.
authors.forename: Canan
authors.initials: C
authors.lastname: Schumann
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University , Portland, Oregon 97201, United States.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Chan
authors.affiliation: Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
authors.forename: Oleh
authors.initials: O
authors.lastname: Khalimonchuk
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University , Portland, Oregon 97201, United States.
authors.forename: Shannon
authors.initials: S
authors.lastname: Khal
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University , Portland, Oregon 97201, United States.
authors.forename: Vitaliya
authors.initials: V
authors.lastname: Moskal
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University , Portland, Oregon 97201, United States.
authors.forename: Vidhi
authors.initials: V
authors.lastname: Shah
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University , Portland, Oregon 97201, United States.
authors.forename: Adam W G
authors.initials: AW
authors.lastname: Alani
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University , Portland, Oregon 97201, United States.
authors.forename: Olena
authors.initials: O
authors.lastname: Taratula
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University , Portland, Oregon 97201, United States.
authors.forename: Oleh
authors.initials: O
authors.lastname: Taratula
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D050091:Dendrimers / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D050997:Nanomedicine / Q000379:methods; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000071617:Protein Deglycase DJ-1 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011966:Receptors, LHRH / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D050091:Dendrimers; D009944:Organoplatinum Compounds; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011966:Receptors, LHRH; D000071617:Protein Deglycase DJ-1; D020169:Caspases
keywords: DJ-1; LHRH; cisplatin; dendrimer; nanomedicine; ovarian cancer; siRNA