Antitumor activity and expression profiles of genes induced by sulforaphane in human melanoma cells

Abstract

PurposeHuman melanoma is a highly aggressive incurable cancer due to intrinsic cellular resistance to apoptosis, reprogramming, proliferation and survival during tumour progression. Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, plays a role in carcinogenesis in many cancer types. However, the cytotoxic molecular mechanisms and gene expression profiles promoted by SFN in human melanoma remain unknown.MethodsThree different cell lines were used: two human melanoma A375 and 501MEL and human epidermal melanocytes (HEMa). Cell viability and proliferation, cell cycle analysis, cell migration and invasion and protein expression and phosphorylation status of Akt and p53 upon SFN treatment were determined. RNA-seq of A375 was performed at different time points after SFN treatment.ResultsWe demonstrated that SFN strongly decreased cell viability and proliferation, induced G2/M cell cycle arrest, promoted apoptosis through the activation of caspases 3, 8, 9 and hampered migration and invasion abilities in the melanoma cell lines. Remarkably, HEMa cells were not affected by SFN treatment. Transcriptomic analysis revealed regulation of genes involved in response to stress, apoptosis/cell death and metabolic processes. SFN upregulated the expression of pro-apoptotic genes, such as p53, BAX, PUMA, FAS and MDM2; promoted cell cycle inhibition and growth arrest by upregulating EGR1, GADD45B, ATF3 and CDKN1A; and simultaneously acted as a potent inhibitor of genotoxicity by launching the stress-inducible protein network (HMOX1, HSPA1A, HSPA6, SOD1).ConclusionOverall, the data show that SFN cytotoxicity in melanoma derives from complex and concurrent mechanisms during carcinogenesis, which makes it a promising cancer prevention agent.Electronic supplementary materialThe online version of this article (doi:10.1007/s00394-017-1527-7) contains supplementary material, which is available to authorized users.

Targeting Phosphorylation of p21-activated Kinase 1 at Thr423 Induces Cell Cycle Arrest and Apoptosis in Cutaneous T-cell Lymphoma Cells

“…EGR1 exhibits a dual role of a tumor suppressor or a tumor-promoting factor in various carcinomas, by regulating cell cycle progression, apoptosis and malignant transformations (19)(20)(21). EGR1 stimulates cells proliferation in prostate, stomach, and kidney cancer (22)(23)(24), whereas it shows a tumor-suppressive activity in breast cancer, melanoma, fibrosarcoma and B cell lymphoma (25)(26)(27)(28). Our results also indicate a tumor-suppressive activity of EGR1 in CTCL.…”

Wasabi 6‐(methylsulfinyl)hexyl isothiocyanate induces apoptosis in human colorectal cancer cells through p53‐independent mitochondrial dysfunction pathway

“…This result is different from that in leukemia cells , in which there was no significant change in total protein level of P53 from 24 to 48 h in 6‐MSITC‐treated cells. On the other hand, treatment with sulforaphane, an analog of 6‐MSITC, also increased the expression level of P53 in prostate cancer cells and melanoma cells , but not in leukemia cells . Therefore, the effects of 6‐MSITC on the protein level of P53 might depend on the cancer cell lines.…”

Brassicaceae-Derived Anticancer Agents: Towards a Green Approach to Beat Cancer

“…Studies have shown that SFN increases the percentage of apoptotic melanoma cells by cleaving poly (ADP-ribose) polymerase (PARP), activating p-p53, caspase-3, caspase-8, and caspase-9, and decreasing Bcl2 expression, thus confirming its pro-apoptotic role. SFN is a very attractive multipotent anti-cancer agent, and its use could open new avenues for preventing tumor growth and treating human malignancies [58]. Sulforaphanes as well as other phytocompounds (e.g., curcumin, epigallocatechin gallate (EGCG), resveratrol, lycopene, SR-T100, several flavonoids, wogonin, Wisteria floribunda agglutinin (WFA), ginsenosides, and genistein derivatives) have been demonstrated to reduce CSC-related marker levels and inhibit CSC-related signaling pathways in ovarian cancer, suggesting their potential use to overcome its chemoresistance and relapse, mainly due to the CSC fraction [76].…”