Functional Analysis of the p53 Pathway in Response to Ionizing Radiation in Uveal Melanoma

Abstract

Expression of p53 and upstream signaling to p53 in response to radiation-induced DNA damage appear to be intact in most uveal melanomas. In contrast, functional defects in the p53 pathway downstream of p53 activation appear to be common. Further elucidation of p53 pathway abnormalities in uveal melanoma may allow therapeutic interventions to increase the radiosensitivity of the tumors.

Molecular Pathology of Uveal Melanoma

“…The p53 pathway is functionally blocked by its inhibitor MDM2 [13][14][15]29,30 BCL-2 Defects in the Bcl2 pathway in UM contribute to apoptosis resistance 11,14,29 PTEN downregulation The PI3K-AKT prosurvival pathway is constitutively activated in UM to avoid apoptosis 19,20 Produce insulin-like growth factor (IGF- …”

“…[11][12][13]29,30,90 The Rb protein is constitutively hyperphosphorylated and functionally inactivated in most UM, probably as a result of cyclin D1 overexpression in about 65% of cases. 12,14,15 ( Figure 1; Table 1) The role of CDKN2A promoter hypermethylation, as an additional mechanism of Rb inactivation, is controversial as the frequency of hypermethylation of this gene varies between 4 and 33% of UM.…”

“…12,[14][15][16]48,74 Increased cyclin D1 protein expression has been associated with larger tumour basal diameter, epithelioid cell type, and poor prognosis. 15 The p53 pathway is inhibited downstream to p53 in many UM, 30 and this may be a consequence of MDM2 overexpression, which is also common in UM and associated with a poor outcome. 13,15 The PI3K/AKT pathway is constitutively activated in most UM 17 (Table 1).…”

Nerve Growth Factor Promotes Endothelial Progenitor Cell-Mediated Angiogenic Responses

“…After 24, 48, and 72 hours of NGF treatment, cells were collected and nonadherent cells were counted manually using the trypan-blue exclusion method. 16 …”

Amfenac increases the radiosensitivity of uveal melanoma cell lines

“…In vitro studies have shown that downstream defects in the p53 pathway may be involved in resistance to apoptosis, even though the radioresistance of UM is unlikely to be attributed to a single genetic defect. 32 UM cell lines show a wide range of radiosensitivity, which may be explained by varied induction of apoptosis, and cell cycle disruption. 33 The mechanism underlying the synergistic effect of COX-2 inhibitors and radiation remains elusive.…”