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 |
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Authors: | Jingwen Yi Xiaoguang Yang Lihua Zheng Guang Yang Luguo Sun Yongli Bao Yin Wu Yanxin Huang Chunlei Yu Shao-Nian Yang Yuxin Li |
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Affiliation: | *National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China;†Jilin Academy of Traditional Chinese Medicine, Changchun 130012, China;‡School of Chemistry, Northeast Normal University, Changchun 130024, China;§The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden |
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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. |
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Keywords: | anti-cancer cell destruction cell growth hypericum perforatum pancreatic endocrine tumour photopharmacology |
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