Radiosensitization of melanoma cells through combined inhibition of protein regulators of cell survival

Abstract

The incidence of melanoma continues to dramatically increase in most Western countries with predominantly Caucasian populations. However, only limited therapies for the metastatic stage of the disease are currently available. The main purpose of this study is to determine approaches that can substantially increase radiosensitivity of melanoma cells. The PI3K-AKT, NF-κB and COX-2 pathways, which are involved in the radioprotective response, are highly active in melanoma cells. Pharmacological suppression of COX-2 and PI3K-AKT, or RNAi-mediated knockdown of COX-2, substantially increased levels of G2/M arrest of the cell cycle and decreased clonogenic survival of gamma-irradiated melanomas, predominantly via a necrotic mechanism. On the other hand, resveratrol, a polyphenolic phytoalexin, selectively targets numerous cell signaling pathways, decreasing clonogenic survival primarily via an apoptotic mechanism. In melanoma cells, resveratrol inhibits STAT3 and NF-κB-dependent transcription, culminating in suppression of cFLIP and Bcl-xL expression, while activating the MAPK-and the ATM-Chk2-p53 pathways. Resveratrol also upregulates TRAIL promoter activity and induces TRAIL surface expression in some melanoma cell lines, resulting in a rapid development of apoptosis. Sequential treatment of melanoma cells, first with γ-irradiation to upregulate TRAIL-R surface expression, and then with resveratrol to suppress antiapoptotic proteins cFLIP and Bcl-xL and induce TRAIL surface expression, had dramatic effects on upregulation of apoptosis in some melanoma lines, including SW1 and WM35. However, for melanoma lines exhibiting suppressed translocation of TRAIL to the cell surface, a necrotic mechanism of cell death was primarily involved in radiation response. Hence, surface expression of TRAIL induced by resveratrol appears to be a decisive event, one HHS Public Access

Role of FK506-binding protein 51 in the control of apoptosis of irradiated melanoma cells

“…26 Given the rising incidence of melanoma and the paucity of effective treatments, there is much hope for targeted therapies and promising agents, including those that act on apoptosisregulating molecules. 11,27 Herein, we showed a novel role for FKBP51 as a marker of melanocyte malignancy and involvement in the protection of melanoma against Rx-induced apoptosis. FKBP51 is a large immunophilin that exerts important biological functions in the cell, among which is the regulation of the steroid hormone response as a component of the steroid hormone receptor complex 28 and the control of NF-kB activation as a cofactor of the IKKa subunit in the IKK complex.…”

“…It is noted that NF-kB controls apoptosis at the genetic level and has been implicated in the radioresistance of melanoma. 11,12 It is widely known that the NF-kB transcription complex belongs to the Rel family, which comprises five mammalian Rel/NF-kB proteins: RelA (p65), c-Rel, RelB, NF-kB1 (p50/p105), and NF-kB2 (p52/100). 13 The activity of NF-kB is controlled by cytoplasmic shuttling to the nucleus in response to cell stimulation.…”

Bcl-XL protein is markedly decreased in UVB-irradiated basal cell carcinoma cell lines through proteasome-mediated degradation

“…Johnson et al reported that melanoma cells were radiosensitized through combined inhibition of protein regulators of cell survival, namely suppression of cFLIP and Bcl-xL expression (15).…”

Signal Transducer and Activator of Transcription 3 - A Promising Target in Colitis-Associated Cancer

“…Rheb-GTP then activates mTORC1, which phosphorylates other downstream targets such as S6 kinase and 4-EBP-1. Akt substrates include Bad, Caspase 9, IKKα, NOS, TSC2, PRAS40, p27, MDM2, and GSK3β (Johnson et al, 2008). Akt mediated phosphorylation of these proteins leads to their activation or inhibition.…”