Adipocytes Contribute to Resistance of Human Melanoma Cells to Chemotherapy and Targeted Therapy
Adipocytes Contribute to Resistance of Human Melanoma Cells to Chemotherapy and Targeted Therapy
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DOI：
10.2174/0929867321666131129114742
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发表时间：
2014-04-01
影响因子：
4.1
通讯作者：
Zhang, X. D.
中科院分区：
文献类型：
--
作者：
Chi, M.;Chen, J.;Zhang, X. D.
流行病学证据表明，包括黑色素瘤在内的多种癌症的发生和进展与肥胖有关。然而，肥胖是否会影响癌细胞对治疗的反应仍不清楚。在这里，我们报告人类脂肪细胞有助于黑色素瘤细胞对各种治疗药物的抵抗。接触脂肪细胞培养物（脂肪细胞培养基）会增加细胞增殖，并降低黑色素瘤细胞对多种化疗药物（包括 DNA 损伤药物顺铂、微管靶向剂多西紫杉醇和组蛋白脱乙酰酶抑制剂 SAHA）诱导的细胞凋亡的敏感性。这与 PI3K/Akt 和 MEK/ERK 信号传导的激活增加有关，并被 PI3K 或 MEK 抑制剂减弱。脂肪细胞培养基对黑色素瘤细胞的作用至少部分归因于脂肪因子瘦素与其长型受体OB-Rb之间的相互作用，脂肪细胞培养基中瘦素的免疫耗竭或黑色素瘤细胞中OB-Rb的siRNA敲低逆转了Akt和ERK活化的增加，细胞增殖的增强，以及重要的是，保护黑色素瘤细胞免受药物的侵害。作为支持，重组瘦素部分重现了脂肪细胞培养基对黑色素瘤细胞的影响。值得注意的是，与黑素细胞相比，黑色素瘤细胞表面的 OB-Rb 增加，而瘦素短型受体似乎在转录后受到抑制，表明 OB-Rb 在黑色素瘤细胞中选择性上调。总的来说，这些结果表明，脂肪细胞有助于黑色素瘤细胞对针对 PI3K/Akt 和 MEK/ERK 途径的化疗药物和药剂的耐药性，并表明抑制瘦素/OB-Rb 系统可能有助于提高多种治疗方法在黑色素瘤治疗中的疗效。
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.