title: Xeroderma Pigmentosum Group A Promotes Autophagy to Facilitate Cisplatin Resistance in Melanoma Cells through the Activation of PARP1.
abstract: 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.
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Ge
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Dai
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Weigang
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Huina
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Sen
authors.initials: S
authors.lastname: Guo
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Yi
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Tianwen
authors.initials: T
authors.lastname: Gao
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China. Electronic address: luanq@foxmail.com.
authors.forename: Qi
authors.initials: Q
authors.lastname: Luan
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China. Electronic address: lichying@fmmu.edu.cn.
authors.forename: Chunying
authors.initials: C
authors.lastname: Li
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects*; D008545:Melanoma / Q000188:drug therapy; D012878:Skin Neoplasms / Q000188:drug therapy; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014983:Xeroderma Pigmentosum / Q000188:drug therapy / Q000235:genetics*; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C556015:PARPBP protein, human; D051760:Xeroderma Pigmentosum Group A Protein; D002945:Cisplatin