title: A synthetic lethal screen identifies the Vitamin D receptor as a novel gemcitabine sensitizer in pancreatic cancer cells.
abstract: Overcoming chemoresistance of pancreatic cancer (PCa) cells should significantly extend patient survival. The current treatment modalities rely on a variety of DNA damaging agents including gemcitabine, FOLFIRINOX, and Abraxane that activate cell cycle checkpoints, which allows cells to survive these drug treaments. Indeed, these treatment regimens have only extended patient survival by a few months. The complex microenvironment of PCa tumors has been shown to complicate drug delivery thus decreasing the sensitivity of PCa tumors to chemotherapy. In this study, a genome-wide siRNA library was used to conduct a synthetic lethal screen of Panc1 cells that was treated with gemcitabine. A sublethal dose (50 nM) of the drug was used to model situations of limiting drug availability to PCa tumors in vivo. Twenty-seven validated sensitizer genes were identified from the screen including the Vitamin D receptor (VDR). Gemcitabine sensitivity was shown to be VDR dependent in multiple PCa cell lines in clonogenic survival assays. Sensitization was not achieved through checkpoint override but rather through disrupting DNA repair. VDR knockdown disrupted the cells' ability to form phospho-γH2AX and Rad51 foci in response to gemcitabine treatment. Disruption of Rad51 foci formation, which compromises homologous recombination, was consistent with increased sensitivity of PCa cells to the PARP inhibitor Rucaparib. Thus inhibition of VDR in PCa cells provides a new way to enhance the efficacy of genotoxic drugs.
authors.affiliation: a Fox Chase Cancer Center ; Institute for Cancer Research ; Philadelphia , PA USA.
authors.forename: V
authors.initials: V
authors.lastname: Bhattacharjee
authors.forename: Y
authors.initials: Y
authors.lastname: Zhou
authors.forename: T J
authors.initials: TJ
authors.lastname: Yen
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015723:Gene Library; D006657:Histones / Q000378:metabolism; D059765:Homologous Recombination; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism*; D051135:Rad51 Recombinase / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071857:Tumor Suppressor p53-Binding Protein 1; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; C468783:H2AX protein, human; D006657:Histones; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D018167:Receptors, Calcitriol; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D003841:Deoxycytidine; C531549:rucaparib; D051135:Rad51 Recombinase; D000093542:Gemcitabine
keywords: BXPC3; DNA DSB, DNA Double-strand break; DNA repair; HDAC inhibitors; IF, Immunofluorescence; PARP inhibitor; PCa, Pancreatic cancer; Panc1; Rad51 foci; VDR; VDR, Vitamin D receptor; Vitamin D receptor; chemosensitization; gemcitabine; p300; pancreatic cancer; siRNA screen; stalled replication fork