title: Lithium chloride has a biphasic effect on prostate cancer stem cells and a proportional effect on midkine levels.
abstract: Prostate cancer (PCa) is the second most frequent type of cancer in men worldwide and the levels of differentiation growth factor midkine (MK) are increased in PCa. Cancer and/or the treatment process itself may lead to psychiatric disorders. Lithium chloride (LiCl) has anti-manic properties and has been used in cancer therapy; however, it has a queried safety profile. In addition, cancer stem cells are responsible for the heterogeneous phenotype of tumor cells; they are involved in progression, metastasis, recurrence and therapy resistance in various cancer types. The aims of the present study were to investigate the effect of different concentrations of LiCl on PCa stem cells (whether a shift from tumorigenic to non-tumorigenic cells occurs) and to determine if these results can be explained through changes in MK levels. Monolayer and spheroid cultures of human prostate stem cells and non-stem cells were incubated with low (1, 10 µM) and high (100, 500 µM) concentrations of LiCl for 72 h. Cell proliferation, apoptotic indices, MK levels and ultrastructure were evaluated. Cells stimulated with low concentrations showed high proliferation, low apoptotic indices, high MK levels and more healthy ultrastructure. Opposite results were obtained at high concentrations. Furthermore, stem cells were more sensitive to stimulation and more resistant to inhibition than non-stem cells. LiCl exhibited concentration-dependent effects on stem cell and non-stem cell groups. MK levels were not involved in the biphasic effect of LiCl; however, they were proportionally affected. To the best of our knowledge, the present study was the first to show the effect of LiCl on PCa stem cells through MK.
authors.affiliation: Department of Medical Biochemistry, Faculty of Medicine, İstanbul Aydın University, Küçükçekmece 34295, İstanbul, Turkey.
authors.forename: Mine
authors.initials: M
authors.lastname: Erguven
authors.affiliation: Department of Histology and Embryology, School of Medicine, Ege University, Bornova 35040, İzmir, Turkey.
authors.forename: Gulperi
authors.initials: G
authors.lastname: Oktem
authors.affiliation: Department of Histology and Embryology, İstanbul Faculty of Medicine, İstanbul University, Capa 34390, İstanbul, Turkey.
authors.forename: Ali Nail
authors.initials: AN
authors.lastname: Kara
authors.affiliation: Department of Histology and Embryology, Emine-Bahaeddin Nakıboğlu Faculty of Medicine, Zirve University, Gaziantep 27260, Turkey.
authors.forename: Ayhan
authors.initials: A
authors.lastname: Bilir
keywords: biphasic effect; cancer stem cell; lithium chloride; midkine; prostate cancer