Abstract
There is a growing interest in the cytotoxic effects of bioactive glycoalkaloids, such as α-tomatine on tumor cells. Here, for the first time, we determine the antitumor potential of tomatine, a mixture of α-tomatine and dehydrotomatine, in metastatic melanoma (MM) cell lines harboring different BRAF and MC1R variants. We performed cytotoxicity experiments and annexin-V/propidium iodide staining to assess the apoptotic/necrotic status of the cells. ER stress and autophagy markers were revealed by Western Blot, whereas antiangiogenic and vascular-disrupting effects were evaluated through a capillary tube formation assay on matrigel and by ELISA kit for VEGF release determination. Cell invasion was determined by a Boyden chamber matrigel assay. Tomatine reduced 50% of cell viability and induced a concentration-dependent increase of apoptotic cells in the range of 0.5–1 μM in terms of α-tomatine. The extent of apoptosis was more than two-fold higher in V600BRAF-D184H/D184H MC1R cells than in BRAF wild-type cells and V600BRAF-MC1R wild-type cell lines. Additionally, tomatine increased the LC3I/II autophagy marker, p-eIF2α, and p-Erk1/2 levels in BRAF wild-type cells. Notably, tomatine strongly reduced cell invasion and melanoma-dependent angiogenesis by reducing VEGF release and tumor-stimulating effects on capillary tube formation. Collectively, our findings support tomatine as a potential antitumor agent in MM.
Highlights
Malignant melanoma is an aggressive type of tumor that mainly occurs on the skin, and it is characterized by poor prognoses for patients with metastatic disease
We previously demonstrated that the activation of such tumorigenic pathways was strictly related to the genetic status of BRAF and melanocortin 1 receptor (MC1R) [1,2,4,5]
endoplasmic reticulum (ER) stress has been associated with variations in tumor angiogenesis [6,7], which is known to play a key role in cancer growth and invasion
Summary
Malignant melanoma is an aggressive type of tumor that mainly occurs on the skin, and it is characterized by poor prognoses for patients with metastatic disease. Glycoalkaloids extracted from plants have been investigated for their pharmaceutical and toxicological properties [10,11]. Among these glycoalkaloids is tomatine, a 10:1 mixture of α-tomatine and dehydrotomatine extracted from tomatoes [12,13]. No data are available regarding the effects of tomatine on metastatic melanoma. We seek to evaluate the antitumor potential of tomatine through the evaluation of its effects on proliferation, cell invasion, and tumor-angiogenesis in metastatic melanoma cells with different genetic contexts, basal autophagy, and the activation status of the α subunit of translation initiation factor 2 (p-eIF2α)
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