Epidemiological evidence has linked the development and progression of several cancers including melanoma
with obesity. However, whether obesity impinges on responses of cancer cells to treatment remains less understood. Here
we report that human adipocytes contribute to resistance of melanoma cells to various therapeutic agents. Exposure to
media from adipocyte cultures (adipocyte media) increased cell proliferation and reduced sensitivity of melanoma cells to
apoptosis induced by diverse chemotherapeutic drugs, including the DNA-damaging drug cisplatin, the microtubuletargeting
agent docetaxel, and the histone deacetylase inhibitor SAHA. This was associated with increased activation of
PI3K/Akt and MEK/ERK signaling, and was attenuated by a PI3K or MEK inhibitor. The effect of adipocyte media on
melanoma cells was, at least in part, due to the interaction between the adipokine leptin and its long form receptor OB-Rb,
in that immunodepletion of leptin in adipocyte media or siRNA knockdown of OB-Rb in melanoma cells reversed the increase
in Akt and ERK activation, enhancement in cell proliferation, and importantly, protection of melanoma cells
against the drugs. In support, recombinant leptin partially recapitulated the effect of adipocyte media on melanoma cells.
Of note, OB-Rb was increased on the surface of melanoma cells compared to melanocytes, whereas leptin short form receptors
appeared to be suppressed post-transcriptionally, suggesting that OB-Rb was selectively upregulated in melanoma
cells. Collectively, these results indicate that adipocytes contribute to the resistance of melanoma cells to chemotherapeutic
drugs and agents targeting the PI3K/Akt and MEK/ERK pathways, and suggest that inhibition of the leptin/ OB-Rb
system may be useful to improve the efficacy of multiple therapeutic approaches in the treatment of melanoma.