Copper-dependent ATP7B up-regulation drives the resistance of TMEM16A-overexpressing head-and-neck cancer models to platinum toxicity.
Copper-dependent ATP7B up-regulation drives the resistance of TMEM16A-overexpressing head-and-neck cancer models to platinum toxicity.
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DOI：
10.1042/bcj20190591
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发表时间：
2019-12-19
期刊：
影响因子：
--
通讯作者：
Kiselyov K
中科院分区：
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作者：
Vyas A;Duvvuri U;Kiselyov K
含铂药物如顺铂和卡铂通常用于治疗许多实体瘤，包括头颈部鳞状细胞癌（SCCHN）。然而，SCCHN对铂化合物的耐药性已得到充分证实。对铂的耐药性与二价转运蛋白ATP 7 B的活性有关，ATP 7 B将铂从细胞质泵入溶酶体，降低其在细胞质中的浓度。几种癌症模型显示ATP 7 B的表达增加;然而，这种增加的原因尚不清楚。在这里，我们显示了在人SCCHN肿瘤中TMEM 16 A和ATP 7 B的mRNA水平之间的强正相关性。SCCHN细胞系中的TMEM 16 A过表达和耗竭引起ATP 7 B mRNA水平的平行变化。TMEM 16 A过表达细胞中的ATP 7 B增加通过抑制NADPH氧化酶2（NOX 2）、通过抗氧化剂N-乙酰半胱氨酸（NAC）以及通过使用铜腙和浴铜灵磺酸盐（BCS）的铜螯合而逆转。用任一螯合剂预处理显著增加顺铂的敏感性，特别是在TMEM 16 A过表达的情况下。我们认为，TMEM 16 A过表达细胞中的氧化应激增加释放了细胞质中的螯合铜，导致ATP 7 B表达的转录激活。这反过来又通过促进铂化合物的囊泡螯合而降低了铂化合物的功效。我们认为，这种对SCCHN肿瘤铂类耐药机制的新解释为治疗这些肿瘤提供了新的途径。
Platinum-containing drugs such as cisplatin and carboplatin are routinely used for the treatment of many solid tumors including squamous cell carcinoma of the head and neck (SCCHN). However, SCCHN resistance to platinum compounds is well documented. The resistance to platinum has been linked to the activity of divalent transporter ATP7B, which pumps platinum from the cytoplasm into lysosomes, decreasing its concentration in the cytoplasm. Several cancer models show increased expression of ATP7B; however, the reason for such an increase is not known. Here we show a strong positive correlation between mRNA levels of TMEM16A and ATP7B in human SCCHN tumors. TMEM16A overexpression and depletion in SCCHN cell lines caused parallel changes in the ATP7B mRNA levels. The ATP7B increase in TMEM16A-overexpressing cells was reversed by suppression of NADPH oxidase 2 (NOX2), by the antioxidant N-Acetyl-Cysteine (NAC) and by copper chelation using cuprizone and bathocuproine sulphonate (BCS). Pretreatment with either chelator significantly increased cisplatin’s sensitivity, particularly in the context of TMEM16A overexpression. We propose that increased oxidative stress in TMEM16A-overexpressing cells liberates the chelated copper in the cytoplasm, leading to the transcriptional activation of ATP7B expression. This, in turn, decreases the efficacy of platinum compounds by promoting their vesicular sequestration. We think that such a new explanation of the mechanism of SCCHN tumors’ platinum resistance identifies novel approach to treating these tumors.