Abstract
This study investigated B16F10 melanoma cell death induced by melatonin combined with endoplasmic reticulum (ER) stress through the PI3K/Akt/mTOR pathway. Cell viability was significantly decreased after treatment with melatonin combined with ER stress from thapsigargin or tunicamycin compared to no treatment or treatment with melatonin only. Combined melatonin and ER stress also significantly reduced expression of p85β, p-Akt (Ser473, Thr308), and p-mTOR (Ser2448, Ser2481) compared to treatment with melatonin only. The ER stress protein p-PERK and p-eIF2α were significantly increased under combined melatonin and ER stress treatment compared to no treatment or treatment with melatonin only. Combined melatonin and ER stress significantly reduced Bcl-2 protein and augmented Bax protein compared to melatonin-only treatment. Also, the combined treatment significantly lowered expression of catalase, Cu/Zn-SOD, and Mn-SOD proteins compared to melatonin only. Expression of p85β was significantly more decreased under treatment with melatonin and thapsigargin or tunicamycin plus the PI3K inhibitors LY294002 or wortmannin than under treatment with only melatonin or a PI3K inhibitor. The PI3K downstream target p-Akt (Ser473, Thr308) showed significantly decreased expression under treatment with melatonin and thapsigargin or tunicamycin plus PI3K inhibitors than under treatment with melatonin or PI3K inhibitors only. These results indicate that survival of B16F10 melanoma cells after combined treatment with melatonin and ER stress inducers is suppressed through regulation of the PI3K/Akt/mTOR pathway. Melatonin combined with thapsigargin or tunicamycin appears to be a promising strategy for effective melanoma treatment.
Highlights
Melanomas are malignant tumors that arise from melanocytes, which produce black or brown melanin pigment in skin, but are found in other parts of the body such as the bowel and the eye
We found that combined melatonin and endoplasmic reticulum (ER) stress treatment induced cell death in B16F10 melanoma cells through the PI3K/Akt/mTOR pathway
We investigated whether melatonin combined with ER stress induced death in B16F10 melanoma cells
Summary
Melanomas are malignant tumors that arise from melanocytes, which produce black or brown melanin pigment in skin, but are found in other parts of the body such as the bowel and the eye. Melanocytes are found in various areas of the body including the skin, bowel, and eyes but are predominantly located in the epidermis; over 90% of all melanomas are cutaneous [1,2,3]. Melatonin has direct anticancer or anti-apoptotic effects on different types of human tumors [6,7,8,9,10,11] and functions as a broadspectrum antioxidant [12,13,14,15,16,17,18]. Numerous studies have demonstrated that melatonin has anti-proliferative effects in melanoma cells [22,23,24,25,26,27,28,29], and that these effects are related to the cell line-specific response of melatonin-binding receptors [25,26,27,28,29]
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