M. I. Chang1,2, P. Nandivada1,2, S. J. Carlson1,2, A. Pan1,2, M. Puder1,2 1Boston Children’s Hospital,Surgery,Boston, MA, USA 2Boston Children’s Hospital,Vascular Biology Program,Boston, MA, USA
Introduction: Melanoma is a neural crest derived tumor and is the most deadly form of skin
cancer. In advanced stages, this and other neural crest tumors (e.g., medullary thyroid,
malignant peripheral nerve sheath tumor, neuroblastoma, etc) have limited treatment options as
they often manifest as aggressive disease. Recent studies have demonstrated cellular
apoptosis in these tumors in the presence of the omega-3 fatty acid, docosahexaenoic acid
(DHA). The purpose of this study is to determine if 1) this effect is mediated through the free
fatty acid G-protein coupled receptor 40 (GPR40) and 2) determine if selective agonism of
GPR40 produces cell death in vitro.
Methods: The presence of the GPR40 receptor was confirmed by PCR and Western blot
analysis on neural crest tumor cell lines including: neuroblastoma, melanoma, medullary thyroid
carcinoma, and malignant peripheral nerve sheath tumor. These cell lines were treated with
varying concentrations of DHA and TAK-875 (a specific, high affinity GPR40 agonist) for 3 and 6
days while using a human fibroblast cell line as a control. Cell viability was determined using an
absorbance-based cell viability assay.
Results: DHA exhibited a minimal inhibitory affect against medullary thyroid carcinoma.
However, cell death was observed in neuroblastoma, melanoma, malignant peripheral nerve
sheath tumor, and fibroblasts at high DHA concentration. TAK-875 produced a profound
selective inhibitory effect on cell proliferation and promoted cell death of all of the neural crest
derived tumor cell lines without toxicity in the control fibroblast line at nanomolar concentrations.
Interestingly, no GPR40 expression was noted in the malignant peripheral nerve sheath tumor.
Conclusion: GPR40 agonist TAK875 produces profound selective cell growth inhibition and
death in neural crest derived tumor cell lines, with reduced cellular toxicity. While the GPR40
receptor may serve as a novel target in the treatment of neural crest-derived tumors, the affect
of this drug on the malignant peripheral nerve sheath tumor may indicate that GPR40 alone may
not be responsible for this dramatic response in cell viability in neural crest-derived tumor cell
lines.