Influence of Melanosome Dynamics on Melanoma Drug Sensitivity
Influence of Melanosome Dynamics on Melanoma Drug Sensitivity
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DOI：
10.1093/jnci/djp259
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发表时间：
2009-09-16
影响因子：
10.3
通讯作者：
Gottesman, Michael M.
中科院分区：
文献类型：
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作者：
Chen, Kevin G.;Leapman, Richard D.;Gottesman, Michael M.
恶性黑色素瘤对许多常规治疗如放射和化疗具有内在的抵抗力，其原因尚不清楚。在这里，我们提出并测试了一个用黑素小体动态来解释耐药性或敏感性的模型。用克隆形成实验比较了黑色素化且富含成熟的III和IV期黑素小体的MNT-1细胞和只有未成熟的I期和II期黑素小体的SK-MEL-28细胞的生长和对顺铂的敏感性。用电子显微镜观察不同细胞系对不同处理的色素沉着、黑素小体阶段、黑素小体数量和细胞结构的差异。比较1-苯基-2-硫脲处理后不同时期黑素小体的相对数量。通过用环孢素类似物PSC-833处理细胞，并通过评估空泡形成和细胞生长抑制来评估药物转运体功能与内源性黑素生成毒性之间的关系。与无色素性SK-MEL-28细胞相比，受损的黑素小体所产生的内源性黑素细胞毒性对MNT-1细胞的生长有明显的抑制作用。MNT-1细胞对顺铂的敏感性是SK-MEL-28细胞的3.8倍(SK-MEL-28和MNT-1细胞的平均IC50分别为2.13微米和0.56微米；差异=1.57微米，95%可信区间=1.45~1.69；P=0.0017)。6.7mU M-CDDP作用72小时后，存活的MNT-1细胞中II-III期黑素小体数量是未处理细胞的6.8倍。用酪氨酸酶抑制剂1-苯基-2-硫脲处理MNT-1细胞，使其转化为早期(II，II-III，III)黑素小体，显著增加了对顺铂的抗性。此外，PSC-833主要通过提高自噬体样空泡结构来抑制MNT-1黑色素瘤细胞的生长，可能是通过抑制黑素体膜转运蛋白。黑素小体的动态(包括其生物发生、密度、状态和结构完整性)调节黑色素瘤细胞的耐药性。操纵黑素小体功能可能是提高抗癌药物对黑色素瘤治疗活性的有效途径。
Malignant melanomas are intrinsically resistant to many conventional treatments, such as radiation and chemotherapy, for reasons that are poorly understood. Here we propose and test a model that explains drug resistance or sensitivity in terms of melanosome dynamics.The growth and sensitivity to cisplatin of MNT-1 cells, which are melanotic and enriched with mature stage III and IV melanosomes, and SK-MEL-28 cells, which have only immature stage I and II melanosomes, were compared using clonogenic assays. Differences in pigmentation, melanosome stages, melanosome number, and cellular structures in different cell lines in response to various treatments were examined by electron microscopy. The relative numbers of melanosomes of different stages were compared after treatment with 1-phenyl-2-thiourea. The relationship between drug transporter function and endogenous melanogenic toxicity was assessed by treating cells with the cyclosporin analog PSC-833 and by assessing vacuole formation and cell growth inhibition. All statistical tests were two-sided.Endogenous melanogenic cytotoxicity, produced by damaged melanosomes, resulted in pronounced cell growth inhibition in MNT-1 cells compared with amelanotic SK-MEL-28 cells. The sensitivity to CDDP of MNT-1 cells was 3.8-fold higher than that of SK-MEL-28 cells (mean IC50 for SK-MEL-28 and MNT-1 = 2.13 mu M and 0.56 mu M, respectively; difference = 1.57 mu M, 95% confidence interval = 1.45 to 1.69; P = .0017). After treatment with 6.7 mu M CDDP for 72 hours, the number of stage II-III melanosomes in surviving MNT-1 cells was 6.8-fold that of untreated cells. Modulation of MNT-1 cells to earlier-stage (II, II-III, III) melanosomes by treatment with the tyrosinase inhibitor 1-phenyl-2-thiourea dramatically increased CDDP resistance. Furthermore, PSC-833 principally suppressed MNT-1 melanotic cell growth via an elevation of autophagosome-like vacuolar structures, possibly by inhibiting melanosome membrane transporters.Melanosome dynamics (including their biogenesis, density, status, and structural integrity) regulate the drug resistance of melanoma cells. Manipulation of melanosome functions may be an effective way to enhance the therapeutic activity of anticancer drugs against melanoma.