Melatonin Combined with Endoplasmic Reticulum Stress Induces Cell Death via the PI3K/Akt/mTOR Pathway in B16F10 Melanoma Cells

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.

Endoplasmic Reticulum Stress Promotes Autophagy and Apoptosis and Reduces Chemotherapy Resistance in Mutant p53 Lung Cancer Cells

“…ERS is well-characterized in human LC [44, 45]. Recent evidence has suggested that ERS can initiate internal pathways that may induce cellular death [27]. The central objective of the ERS response is to limit disturbance and ultimately recover ER balance; however, in terms of intense or sustained ERS, these pathways will activate programmed cell apoptosis [46].…”

“…ERS shares a correlation with the PI3K/Akt/mTOR signaling pathway. Our experimental data revealed that increases in ERS are followed by decreases in PI3K/AKT/mTOR signaling, as well as reductions in chemoresistance; when the PI3K/AKT/mTOR signaling pathway is blocked, autophagy and apoptosis factors are increased, chemotherapy resistance is weakened, and the tumor shrinks [27, 59], which has an important function in autophagy and apoptosis regulation [2, 60, 61]. It has been reported that blocking the PI3K/AKT/mTOR cascade promotes autophagy [62] that inhibiting PI3K/Akt/mTOR signaling promotes cell apoptosis in LC [28], which is consistent with our results.…”

“…The phosphatidyl inositol 3-kinase/mammalian target of rapamycin/protein kinase B (PI3K/ mTOR/AKT) pathway plays a crucial role in many cancers, including LC, thyroid carcinoma, breast cancer, and cervical cancer [22-26]. Along with the downstream targets AKT and mTOR, PI3K is plays a central role for various physiological processes, such as cell growth, cell motility, cell survival, proliferation, differentiation, as well as in the progression of malignant disease [27]. The PI3K/Akt/mTOR pathway is known to be involved in human LC [28-30], however the finer mechanisms through by which ERS and the PI3K/Akt/mTOR pathway collaborate in mutant p53 LC are still under investigation.…”

Anti-cancer effects of enteric-coated polymers containing mistletoe lectin in murine melanoma cells in vitro and in vivo

“…Melanoma is a malignant tumor that arises from melanocytes, which produce black or brown melanin pigment in skin, bowel, and eyes, but over 90 % of all melanomas are cutaneous [40][41][42][43]. Despite significant progress in melanoma research over the years, there are no effective therapies for advanced melanoma at present [44][45][46].…”

Molecular aspects of melatonin (MLT)-mediated therapeutic effects

“…Cellcycle study on osteocarcinoma MG-63 cell lines showed that MLT treatment arrests cells in G1 and G2/M phase of the cell cycle by the down-regulation of cyclin D1, CDK4, cyclin B and CDK1 (Liu et al, 2013). Similarly, MLT down-regulates the PI3K/AKT/mTOR (mammalian target of rapamycin) signalling pathway in B16F10 melanoma, which has been known for the proteosomal degradation of p27 (Kim et al, 2014). Furthermore, the flow- …”