Melatonin combined with endoplasmic reticulum stress induces cell death via the PI3K/Akt/mTOR pathway in B16F10 melanoma cells

• Published in: PloS one 2014-03, Vol.9 (3), p.e92627-e92627
• Main Authors: Kim, Han Sung, Kim, Tack-Joong, Yoo, Yeong-Min
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Animals; Apoptosis; BAX protein; Bcl-2 protein; Biochemistry; Biology and life sciences; Biomedical engineering; Biotechnology; Cancer therapies; Catalase; Cell death; Cell Death - physiology; Cell Line, Tumor; Cell survival; Cell Survival - drug effects; Combined treatment; Comparative analysis; Copper; Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; Endoplasmic Reticulum Stress - genetics; Endoplasmic Reticulum Stress - physiology; Inhibitors; Investigations; Kinases; Lymphoma; Manganese; Medicine and Health Sciences; Melanoma; Melatonin; Melatonin - pharmacology; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Proteins; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Rodents; Science; Skin cancer; Stress; Stresses; Superoxides; Thapsigargin; TOR protein; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Tumors; Tunicamycin; Wortmannin; Zinc
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0092627

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.