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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
Vitamin E δ-tocotrienol triggers endoplasmic reticulum stress-mediated apoptosis in human melanoma cells
Marina Montagnani Marelli1, Monica Marzagalli1, Roberta M Moretti1
1Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milano, 20133, Italy.
Abstract:
Malignant melanoma is the leading cause of death from skin cancer. Drug toxicity and resistance represent a serious challange for melanoma treatments. Evidence demonstrates that natural compounds may play a crucial role in cancer prevention, growth and progression. Vitamin E tocotrienols (TT) were shown to possess antitumor activity. Here, we analyzed the effects of δ-TT on melanoma cell growth and the involvement of the endoplasmic reticulum (ER) stress in this activity. The experiments were performed on human melanoma cell lines, BLM and A375. δ-TT exerted a significant proapoptotic effect on both cell lines, involving the intrinsic apoptosis pathway; importantly, this compound did not affect the viability of normal human melanocytes. In melanoma cells, δ-TT exerted its antitumor effect through activation of the PERK/p-eIF2α/ATF4/CHOP, IRE1α and caspase-4 ER stress-related branches. Salubrinal, an inhibitor of the ER stress, counteracted the cytotoxic activity of δ-TT. In vivo experiments performed in nude mice bearing A375 xenografts evidenced that δ-TT reduces tumor volume and tumor mass; importantly, tumor progression was significantly delayed by δ-TT treatment. In conclusion, δ-TT exerts a proapoptotic activity on melanoma cells, through activation of the ER stress-related pathways. δ-TT might represent an effective option for novel chemopreventive/therapeutic strategies for melanoma.
Insights
Delta-tocotrienol (δ-TT) shows promise as a melanoma treatment by inducing cancer cell death and reducing tumor growth. This natural compound activates endoplasmic reticulum stress pathways without harming normal melanocytes.
Area of Science:
- Oncology
- Molecular Biology
- Natural Products Chemistry
Background:
- Malignant melanoma is a deadly skin cancer with significant treatment challenges due to drug resistance and toxicity.
- Natural compounds are increasingly recognized for their potential in cancer prevention and therapy.
- Vitamin E tocotrienols (TT) exhibit antitumor properties, warranting further investigation.
Purpose of the Study:
- To investigate the effects of delta-tocotrienol (δ-TT) on melanoma cell growth.
- To elucidate the role of endoplasmic reticulum (ER) stress in δ-TT's anti-melanoma activity.
- To evaluate the therapeutic potential of δ-TT in preclinical melanoma models.
Main Methods:
- Experiments were conducted on human melanoma cell lines (BLM and A375) and normal human melanocytes.
- Assessed the proapoptotic effects of δ-TT and its impact on the intrinsic apoptosis pathway.
- Analyzed the activation of ER stress pathways (PERK, IRE1α, caspase-4) and the effect of salubrinal (ER stress inhibitor).
- Evaluated δ-TT efficacy in vivo using A375 xenograft nude mouse models.
Main Results:
- δ-TT demonstrated significant proapoptotic effects on melanoma cells but not on normal melanocytes.
- The anti-melanoma activity of δ-TT was mediated by the activation of ER stress-related pathways.
- Inhibition of ER stress by salubrinal counteracted the cytotoxic effects of δ-TT.
- In vivo studies showed that δ-TT reduced tumor volume and mass, significantly delaying tumor progression.
Conclusions:
- δ-TT exerts a proapoptotic effect on melanoma cells via the activation of ER stress pathways.
- δ-TT exhibits a selective cytotoxic effect, sparing normal melanocytes.
- δ-TT demonstrates potential as a novel chemopreventive or therapeutic agent for melanoma treatment.
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