Growth Hormone Upregulates Melanocyte-Inducing Transcription Factor Expression and Activity via JAK2-STAT5 and SRC Signaling in GH Receptor-Positive Human Melanoma.

Growth Hormone Upregulates Melanocyte-Inducing Transcription Factor Expression and Activity via JAK2-STAT5 and SRC Signaling in GH Receptor-Positive Human Melanoma.

Publication date: Sep 12, 2019

Growth hormone (GH) facilitates therapy resistance in the cancers of breast, colon, endometrium, and melanoma. The GH-stimulated pathways responsible for this resistance were identified as suppression of apoptosis, induction of epithelial-to-mesenchymal transition (EMT), and upregulated drug efflux by increased expression of ATP-binding cassette containing multidrug efflux pumps (ABC-transporters). In extremely drug-resistant melanoma, ABC-transporters have also been reported to mediate drug sequestration in intracellular melanosomes, thereby reducing drug efficacy. Melanocyte-inducing transcription factor (MITF) is the master regulator of melanocyte and melanoma cell fate as well as the melanosomal machinery. MITF targets such as the oncogene MET, as well as MITF-mediated processes such as resistance to radiation therapy, are both known to be upregulated by GH. Therefore, we chose to query the direct effects of GH on MITF expression and activity towards conferring chemoresistance in melanoma. Here, we demonstrate that GH significantly upregulates MITF as well as the MITF target genes following treatment with multiple anticancer drug treatments such as chemotherapy, BRAF-inhibitors, as well as tyrosine-kinase inhibitors. GH action also upregulated MITF-regulated processes such as melanogenesis and tyrosinase activity. Significant elevation in MITF and MITF target gene expression was also observed in mouse B16F10 melanoma cells and xenografts in bovine GH transgenic (bGH) mice compared to wild-type littermates. Through pathway inhibitor analysis we identified that both the JAK2-STAT5 and SRC activities were critical for the observed effects. Additionally, a retrospective analysis of gene expression data from GTEx, NCI60, CCLE, and TCGA databases corroborated our observed correlation of MITF function and GH action. Therefore, we present in vitro, in vivo, and in silico evidence which strongly implicates the GH-GHR axis in inducing chemoresistance in human melanoma by driving MITF-regulated and ABC-transporter-mediated drug clearance pathways.

Basu, R., Kulkarni, P., Qian, Y., Walsh, C., Arora, P., Davis, E., Duran-Ortiz, S., Funk, K., Ibarra, D., Kruse, C., Mathes, S., McHugh, T., Brittain, A., Berryman, D.E., List, E.O., Okada, S., and Kopchick, J.J. Growth Hormone Upregulates Melanocyte-Inducing Transcription Factor Expression and Activity via JAK2-STAT5 and SRC Signaling in GH Receptor-Positive Human Melanoma. 24414. 2019 Cancers (Basel) (11):9.

Concepts Keywords
ABC Transporter Machinery
ABC Transporters MITF SRC sarcoma
Apoptosis Chemoresistance melanoma
ATP Binding Cassette B16F10 melanoma
Basel Radiation therapy
Bovine Chemotherapy
BRAF Branches of biology
Breast Transcription factors
Chemoresistance Gene expression
Chemotherapy Tyrosine kinases
Colon Microphthalmia-associated transcription factor
Correlation Proteins
Efflux Pumps Janus kinase 2
EMT STAT5
Endometrium Melanoma
Epithelial Growth hormone
Growth Hormone Radiation
Inhibitor Apoptosis
Intracellular Chemotherapy
JAK2
Melanocyte
Melanogenesis
Melanoma
Melanosomes
Mesenchymal
MITF
Oncogene
Radiation Therapy
SRC
STAT5
Transcription Factor
Transgenic
Tyrosinase
Tyrosine Kinase
Vivo
Wild Type
Xenografts

Semantics

Type Source Name
gene UNIPROT SOAT1
disease DOID sarcoma
disease MESH sarcoma
pathway BSID Gene Expression
pathway BSID Melanogenesis
drug DRUGBANK L-Tyrosine
gene UNIPROT BRAF
gene UNIPROT MET
gene UNIPROT SLTM
drug DRUGBANK Methionine
gene UNIPROT FATE1
gene UNIPROT MITF
drug DRUGBANK Abacavir
drug DRUGBANK ATP
gene UNIPROT SLC22A3
gene UNIPROT ITK
pathway BSID Apoptosis
disease MESH cancers
pathway BSID Melanoma
disease DOID Melanoma
disease MESH Melanoma
gene UNIPROT GHR
gene UNIPROT SRC
gene UNIPROT STAT5A
gene UNIPROT JAK2
gene UNIPROT GH1
drug DRUGBANK Somatotropin

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