Cell Cycle Phase-Specific Drug Resistance as an Escape Mechanism of Melanoma Cells
Cell Cycle Phase-Specific Drug Resistance as an Escape Mechanism of Melanoma Cells
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DOI：
10.1016/j.jid.2016.02.805
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发表时间：
2016-07-01
影响因子：
6.5
通讯作者：
Haass, Nikolas K.
中科院分区：
文献类型：
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作者：
Beaumont, Kimberley A.;Hill, David S.;Haass, Nikolas K.
肿瘤微环境的特征在于具有异质细胞周期谱的癌细胞亚群。例如，缺氧肿瘤区含有停滞在G（1）期的癌细胞簇。可以想象，肿瘤细胞基于其在特定细胞周期阶段的驻留而表现出不同的药物敏感性。在这项研究中，我们使用二维和器官型黑色素瘤培养模型结合荧光细胞周期指标，以研究细胞周期阶段对临床使用的药物的影响。我们证明，G（1）-阻滞的黑色素瘤细胞，不管介导G（1）阻滞的根本原因，是抵抗蛋白酶体抑制剂硼替佐米或烷化剂替莫唑胺诱导的细胞凋亡。相反，G（1）-阻滞细胞对丝裂原活化蛋白激酶途径激活剂诱导的细胞死亡更敏感。具有临床意义的是，用丝裂原活化蛋白激酶途径抑制剂预处理黑色素瘤细胞，诱导G（1）阻滞，导致对替莫唑胺或硼替佐米的耐药性。另一方面，替莫唑胺预处理可诱导G（2）阻滞，但不会导致对丝裂原活化蛋白激酶途径抑制剂的耐药性。综上所述，我们建立了一个研究细胞周期对药物敏感性影响的模型。细胞周期阶段特异性耐药性是黑色素瘤细胞的逃逸机制，其对药物联合治疗的选择和时机具有影响。
The tumor microenvironment is characterized by cancer cell subpopulations with heterogeneous cell cycle profiles. For example, hypoxic tumor zones contain clusters of cancer cells that arrest in G(1) phase. It is conceivable that neoplastic cells exhibit differential drug sensitivity based on their residence in specific cell cycle phases. In this study, we used two-dimensional and organotypic melanoma culture models in combination with fluorescent cell cycle indicators to investigate the effects of cell cycle phases on clinically used drugs. We demonstrate that G(1)-arrested melanoma cells, irrespective of the underlying cause mediating G(1) arrest, are resistant to apoptosis induced by the proteasome inhibitor bortezomib or the alkylating agent temozolomide. In contrast, G(1)-arrested cells were more sensitive to mitogen-activated protein kinase pathway inhibitor-induced cell death. Of clinical relevance, pretreatment of melanoma cells with a mitogen-activated protein kinase pathway inhibitor, which induced G(1) arrest, resulted in resistance to temozolomide or bortezomib. On the other hand, pretreatment with temozolomide, which induced G(2) arrest, did not result in resistance to mitogen-activated protein kinase pathway inhibitors. In summary, we established a model to study the effects of the cell cycle on drug sensitivity. Cell cycle phase-specific drug resistance is an escape mechanism of melanoma cells that has implications on the choice and timing of drug combination therapies.