Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

Abstract

Although many human melanomas express the death receptors TRAIL-R2/DR5 or TRAIL-R1/ DR4 on cell surface, they often exhibit resistance to exogenous TRAIL. One of the main contributors to TRAIL-resistance of melanoma cells is upregulation of transcription factors STAT3 and NF-κB that control the expression of antiapoptotic genes, including cFLIP and BclxL. On the other hand, the JNK-cJun pathway is involved in the negative regulation of cFLIP (a caspase-8 inhibitor) expression. Our observations indicated that resveratrol, a polyphenolic phytoalexin, decreased STAT3 and NF-κB activation, while activating JNK-cJun that finally suppressed expression of cFLIP and Bcl-xL proteins and increased sensitivity to exogenous TRAIL in DR5-positive melanomas. Interestingly, resveratrol did not increase surface expression of DR5 in human melanomas, while γ-irradiation or sodium arsenite treatment substantially upregulated DR5 expression. Hence, an initial increase in DR5 surface expression (either by γ-irradiation or arsenite), and subsequent downregulation of antiapoptotic cFLIP and Bcl-xL (by resveratrol), appear to constitute an efficient approach to reactivate apoptotic death pathways in TRAIL-resistant human melanomas. In spite of partial suppression of mitochondrial function and the mitochondrial death pathway, melanoma cells still retain the potential to undergo the DR5-mediated, caspase-8-dependent death pathway that could be accelerated by either an increase in DR5 surface expression or suppression of cFLIP. Taken together, these results suggest that resveratrol, in combination with TRAIL, may have a significant efficacy in the treatment of human melanomas.

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

“…Furthermore, RV by itself was an efficient inducer of apoptotic death in some cancer cell lines [28], including melanoma lines [17]. We observed that RV upregulated TRAIL gene promoter activity and induced TRAIL surface expression that was quite diverse in different melanoma lines (Fig.…”

“…Hence, RV via its effects on the main signaling pathways in melanoma cells resulting in strong downregulation of levels of antiapoptotic proteins, such as cFLIP-L (caspase-8 inhibitor) and Bcl-xL (Fig. 6c), can sensitize these cells to TRAIL-mediated apoptosis [17]. Knockdown of cFLIP levels by the specific RNAi also sensitizes SW1 cells to TRAIL-mediated apoptosis (data not shown).…”

“…There is a profound qualitative similarity in action of RV on signaling pathways in human LU1205 [29] and murine SW1 melanoma cells (Fig. 6c).…”

“…Our recent finding demonstrates that resveratrol (RV), a polyphenolic phytoalexin, may accelerate exogenous TRAIL induced death in many melanoma cell lines [17]. Furthermore, RV by itself was an efficient inducer of apoptotic death in some cancer cell lines [28], including melanoma lines [17].…”

“…However, p53 does not appear to play a direct role in executive regulation of apoptosis via p53-dependent BH3-only proteins (PUMA, NOXA) or p53-dependent BAX in many melanoma lines. This lack of proapoptotic p53 influence is due to downstream protective mechanisms, such as cancerspecific suppression of mitochondrial function and the mitochondrial death pathway [15,16] that was often observed in advanced melanomas [17].…”