Pharmacological attenuation of melanoma by tryptanthrin pertains to the suppression of MITF-M through MEK/ERK signaling axis

Melanoma is the most aggressive among all types of skin cancers. The current strategies against melanoma utilize BRAF V600E , as a focal point for targeted therapy. However, therapy resistance developed in melanoma patients against the conventional anti-melanoma drugs hinders the ultimate benefits o...

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Published in:Cellular and molecular life sciences : CMLS 2022-09, Vol.79 (9), p.478-478, Article 478
Main Authors: Shabna, Anwar, Antony, Jayesh, Vijayakurup, Vinod, Saikia, Minakshi, Liju, Vijayasteltar B., Retnakumari, Archana P., Amrutha, Nisthul A., Alex, Vijai V., Swetha, Mundanattu, Aiswarya, Sreekumar U., Jannet, Somaraj, Unni, Uma Subramanian, Sundaram, Sankar, Sherin, Daisy R., Anto, Nikhil Ponnoor, Bava, Smitha V., Chittalakkottu, Sadasivan, Ran, Sophia, Anto, Ruby John
Format: Article
Language:English
Subjects:
Animal models
Animals
Anticancer properties
Antitumor agents
Attenuation
Biochemistry
Biomedical and Life Sciences
Biomedicine
Casein
Cell Biology
Cell Line, Tumor
Cell Proliferation
Extracellular signal-regulated kinase
Gene expression
Gene Expression Regulation, Neoplastic
Homeostasis
Humans
In vivo methods and tests
Kinases
Life Sciences
MAP Kinase Signaling System
Melanoma
Melanoma - genetics
Metastases
Metastasis
Mice
Microphthalmia-associated transcription factor
Microphthalmia-Associated Transcription Factor - genetics
Microphthalmia-Associated Transcription Factor - metabolism
Mitogen-Activated Protein Kinase Kinases - metabolism
Network analysis
Original
Original Article
Pharmacology
Proto-Oncogene Proteins B-raf - genetics
Proto-Oncogene Proteins B-raf - metabolism
Quinazolines
Signaling
String protein
Survival
Therapy
Transcription activation
Transcription factors
Tumors
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Summary:Melanoma is the most aggressive among all types of skin cancers. The current strategies against melanoma utilize BRAF V600E , as a focal point for targeted therapy. However, therapy resistance developed in melanoma patients against the conventional anti-melanoma drugs hinders the ultimate benefits of targeted therapies. A major mechanism by which melanoma cells attain therapy resistance is via the activation of microphthalmia-associated transcription factor-M (MITF-M), the key transcription factor and oncogene aiding the survival of melanoma cells. We demonstrate that tryptanthrin (Tpn), an indole quinazoline alkaloid, which we isolated and characterized from Wrightia tinctoria , exhibits remarkable anti-tumor activity towards human melanoma through the down-regulation of MITF-M. Microarray analysis of Tpn-treated melanoma cells followed by a STRING protein association network analysis revealed that differential expression of genes in melanoma converges at MITF-M. Furthermore, in vitro and in vivo studies conducted using melanoma cells with differential MITF-M expression status, endogenously or ectopically, demonstrated that the anti-melanoma activity of Tpn is decisively contingent on its efficacy in down-regulating MITF-M expression. Tpn potentiates the degradation of MITF-M via the modulation of MEK1/2-ERK1/2-MITF-M signaling cascades. Murine models demonstrate the efficacy of Tpn in attenuating the migration and metastasis of melanoma cells, while remaining pharmacologically safe. In addition, Tpn suppresses the expression of mutated BRAF V600E and inhibits Casein Kinase 2α, a pro-survival enzyme that regulates ERK1/2 homeostasis in many tumor types, including melanoma. Together, we point to a promising anti-melanoma drug in Tpn, by virtue of its attributes to impede melanoma invasion and metastasis by attenuating MITF-M.
ISSN:1420-682X
1420-9071
DOI:10.1007/s00018-022-04476-y