Sulforaphane-induced apoptosis involves p53 and p38 in melanoma cells

Abstract

In malignant melanoma complex reprogramming of cell death and survival pathways leads to increased chemoresistance and poor longer-term survival. Sulforaphane (SF) is a promising isothiocyanate compound occurring in cruciferous plants with reported antiproliferative and proapoptotic activity in several tumor cell lines including melanoma. In this work we investigated the effects of SF in several melanoma cell lines and fresh melanoma cultivates. We found that SF is cytotoxic and induces mitochondrial, caspase-dependent apoptosis in our study model, however with lower efficiency in fresh melanoma cultivates. Moreover, our results indicate that in melanoma cell lines and fresh melanoma cultivates SF induces multiple signaling including oxidative stress-mediated activation of DNA-damage response pathway, changes in p38 kinase activity and enhanced expression of Bax and Puma proapoptotic proteins. In addition, in SF-exposed p53-mutant melanoma cells Puma expression seem to be under p38 control and acts as a compensatory proapoptotic mechanism. Conversely, decreased apoptosis in SF-exposed melanoma cultivates might be attributed to Akt-mediated suppression of p38 as well as p53 activity. Together, our results suggest that SF inhibits growth and proliferation and induces mitochondrial apoptosis both in melanoma cell lines as well as in fresh melanoma cultivates. This proapoptotic effect might be enhanced in combination with Akt inhibitors, in particular in melanoma samples. SF is thus commendable for further preclinical testing, both as a single agent as well as in combination regimens.

The Ezh2 polycomb group protein drives an aggressive phenotype in melanoma cancer stem cells and is a target of diet derived sulforaphane

“…SFN is a diet-derived natural agent, present in cruciferous vegetables, that suppresses cancer formation in several systems [29,50,[58][59][60][61][62]. Previous studies suggest that SFN suppresses survival of melanoma cancer cells via mechanisms that involve induction of apoptosis [34,35]. However, the impact on MCS cells has not been studied.…”

“…SFN is a particularly appealing as a cancer prevention and treatment agent, as it is highly bioavailable in blood and tissues and has no known side effects [30][31][32][33]. SFN has been shown to modulate the melanoma tumor environment and may be an important prevention/treatment option [34][35][36][37][38].…”

Sulforaphane suppresses cell growth and collagen expression of keloid fibroblasts

“…It was reported that sulforaphane was a highly potent inducer of phase 2 cytoprotective enzymes and played a role in protecting against carcinogenesis, oxidative stress, and inflammation . Recent studies have suggested that sulforaphane could inhibit tumor growth in various cancer cells . The accumulated evidence discusses mechanisms for the cell‐cycle arrest and apoptosis induction by sulforaphane, as one of the mechanisms; inhibition of histone deacetylase (HDAC) by sulforaphane has been shown in human cancer cells .…”

Role of EZH2 in cancer stem cells: from biological insight to a therapeutic target

“…It was reported that EGCG reduced EZH2 expression levels by increasing proteasomal degradation [121, 122]. In addition, sulforaphane (SFN), a natural tumor-preventing compound extracted from broccoli and other cruciferous vegetables [123] was shown to induce apoptosis in melanoma tumor cells and have significant therapeutic potential in skin cancer [124–126]. Previous reports identified that SFN could decrease expression of EZH2 through a proteasome-dependent mechanism [122, 127].…”