Xeroderma Pigmentosum Group A Promotes Autophagy to Facilitate Cisplatin Resistance in Melanoma Cells through the Activation of PARP1
Xeroderma Pigmentosum Group A Promotes Autophagy to Facilitate Cisplatin Resistance in Melanoma Cells through the Activation of PARP1
复制标题
XPA 通过激活 PARP1 促进自噬，促进黑色素瘤细胞对顺铂产生耐药性
DOI：
10.1016/j.jid.2016.01.031
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发表时间：
2016-06-01
影响因子：
6.5
通讯作者：
Li, Chunying
中科院分区：
文献类型：
--
作者：
Ge, Rui;Liu, Lin;Li, Chunying
着色性干皮病A组（XPA），核苷酸切除修复途径中的关键蛋白，已被证明通过促进DNA修复过程来促进肿瘤细胞对化疗药物的抗性。然而，XPA在黑色素瘤对顺铂等铂类药物耐药性中的作用在很大程度上是未知的。在这项研究中，我们最初发现XPA在顺铂耐药的黑色素瘤细胞中的表达水平高于顺铂敏感的黑色素瘤细胞。此外，敲低XPA不仅增加细胞凋亡，而且抑制顺铂诱导的自噬，这使得黑素瘤细胞对顺铂更敏感。此外，我们发现耐药黑色素瘤细胞中增加的XPA促进聚（腺苷二磷酸-核糖）聚合酶1（PARP 1）的活化，并且抑制PARP 1可以减弱顺铂诱导的自噬。最后，我们证明了PARP 1的抑制和自噬过程使耐药黑色素瘤细胞对顺铂治疗更敏感。我们的研究表明，XPA可以通过增强对顺铂耐药的黑色素瘤细胞中PARP 1的活化，以DNA修复无关的方式促进细胞保护性自噬，并且XPA-PARP 1介导的自噬过程可以靶向克服黑色素瘤化疗中的顺铂耐药性。
Xeroderma pigmentosum group A (XPA), a key protein in the nucleotide excision repair pathway, has been shown to promote the resistance of tumor cells to chemotherapeutic drugs by facilitating the DNA repair process. However, the role of XPA in the resistance of melanoma to platinum-based drugs like cisplatin is largely unknown. In this study, we initially found that XPA was expressed at higher levels in cisplatin-resistant melanoma cells than in cisplatin-sensitive ones. Furthermore, the knockdown of XPA not only increased cellular apoptosis but also inhibited cisplatin-induced autophagy, which rendered the melanoma cells more sensitive to cisplatin. Moreover, we discovered that the increased XPA in resistant melanoma cells promoted poly(adenosine diphosphate-ribose) polymerase 1 (PARP1) activation and that the inhibition of PARP1 could attenuate the cisplatin-induced autophagy. Finally, we proved that the inhibition of PARP1 and the autophagy process made resistant melanoma cells more susceptible to cisplatin treatment. Our study shows that XPA can promote cell-protective autophagy in a DNA repair-independent manner by enhancing the activation of PARP1 in melanoma cells resistant to cisplatin and that the XPA-PARP1-mediated autophagy process can be targeted to overcome cisplatin resistance in melanoma chemotherapy.