Adipocytes Contribute to Resistance of Human Melanoma Cells to Chemotherapy and Targeted Therapy

Abstract

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.

Obesity, adipokines and cancer: an update

“…44,58 Recently, there have been more studies looking into the association between leptin and malignant melanoma. 59,60 Leptin was found not only to correlate positively with the risk of developing malignant melanoma, but also accelerate tumour growth. Interestingly, it has been proposed that serum leptin-receptor levels might possibly be employed as a new tumour marker of malignant melanoma as its levels are inversely associated with the stage of the disease, with highest levels found at the in situ stage and lowest at stage IV.…”

Weight control interventions improve therapeutic efficacy of dacarbazine in melanoma by reversing obesity-induced drug resistance

“…Importantly, there is a molecular link between FASN, Cav-1, and P-gp signaling pathways which is regulated by adipokine-driven Akt activation under obese state. We have previously reported that FASN and Cav-1 interact with each other and are regulated by adipokines [23]. FASN modulates Cav-1-dependent signaling pathways and controls proliferation of cancer cells [42].…”

“…Insulin, leptin, and adiponectin levels in the serum were estimated by mouse-specific respective ELISA kits as described [23]. Resistin, IL-6, and TNF-α levels in the serum were detected by indirect ELISA as described previously [27].…”

“…In addition, tumor type and degree of adiposity add up to the complexity of therapy and further restrict the choices of chemotherapeutic drugs under obesity [20]. Contribution of adipocytes to chemoresistance of melanoma involves multiple signaling pathways and, hence, is difficult to target them all [23]. …”

The features of leptin and its receptor expression in metastatic cutaneous melanoma

“…Оказалось, что инкубация клеток мела-номы в среде после культивирования в ней адипоцитов повышает уровень клеточной пролиферации и рези-стентность меланомы к ДНК-повреждающему препа-рату цисплатину, а также к доцетакселу и к ингибитору гистоновой деацетилазы SAHA посредством активации сигнальных каскадов PI3K / AKT и MEK / ERK, осла-бляющих действие ингибиторов PI3K или MEK. Инги-бирование взаимодействия Lep-LepR, избирательно активированного в клетках меланомы, может повысить терапевтическое действие препаратов, нацеленных на перечисленные сигнальные пути [9].…”