title: Photoactivation of hypericin decreases the viability of RINm5F insulinoma cells through reduction in JNK/ERK phosphorylation and elevation of caspase-9/caspase-3 cleavage and Bax-to-Bcl-2 ratio.
abstract: Insulinomas cause neuroglycopenic symptoms, permanent neurological damage and even death. Current available therapies cannot satisfactorily treat malignant insulinomas and some benign insulinomas. The promising phototherapeutic results and harmless side effects of hypericin in some cancer treatments prompted us to explore possible anti-growth activity of photoactivated hypericin against RINm5F insulinoma cells and underlying mechanisms. We now show that detectable and maximal internalization of hypericin in RINm5F insulinoma cells occurred in 20 and 60 min respectively. Hypericin was considerably associated with the plasma membrane, appreciably localized in the sub-plasma membrane region and substantially accumulated in the cytoplasm. Photoactivated hypericin decreased the viability of RINm5F insulinoma cells due to its anti-proliferative and apoptotic actions. Photoactivation of hypericin inhibited cell proliferation reflected by decreased expression of the proliferation marker Ki-67 and cell-cycle arrest in the G0/G1-phase. The anti-proliferative effect resulted from down-regulation of phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular-signal-regulated kinase (ERK). Photoactivated hypericin triggered apoptosis through activation of caspase-3 and caspase-9 and elevation of the Bax-to B-cell lymphoma 2 (Bcl-2) ratio. The findings lay a solid foundation for implementation of hypericin-mediated photodynamic therapy in treatment of insulinomas.
authors.affiliation: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Yi
authors.affiliation: School of Chemistry, Northeast Normal University, Changchun 130024, China liyx486@nenu.edu.cn yangxg168@nenu.edu.cn shao-nian.yang@ki.se.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Yang
authors.affiliation: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Jilin Academy of Traditional Chinese Medicine, Changchun 130012, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.affiliation: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China.
authors.forename: Luguo
authors.initials: L
authors.lastname: Sun
authors.affiliation: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China.
authors.forename: Yongli
authors.initials: Y
authors.lastname: Bao
authors.affiliation: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Wu
authors.affiliation: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China.
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Huang
authors.affiliation: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China.
authors.forename: Chunlei
authors.initials: C
authors.lastname: Yu
authors.affiliation: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden liyx486@nenu.edu.cn yangxg168@nenu.edu.cn shao-nian.yang@ki.se.
authors.forename: Shao-Nian
authors.initials: SN
authors.lastname: Yang
authors.affiliation: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China liyx486@nenu.edu.cn yangxg168@nenu.edu.cn shao-nian.yang@ki.se.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D000873:Anthracenes; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007340:Insulinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010569:Perylene / Q000031:analogs & derivatives* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000873:Anthracenes; C494828:Bax protein, rat; D017319:Photosensitizing Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D010569:Perylene; C004965:hypericin; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4; D053148:Caspase 3; D053453:Caspase 9
keywords: anti-cancer; cell destruction; cell growth; hypericum perforatum; pancreatic endocrine tumour; photopharmacology