PARP1 Upregulation in Recurrent Oral Cancer and Treatment Resistance.
PARP1 Upregulation in Recurrent Oral Cancer and Treatment Resistance.
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DOI：
10.3389/fcell.2021.804962
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发表时间：
2021
影响因子：
5.5
通讯作者：
Peng A
中科院分区：
文献类型：
--
作者：
Wang F;Gouttia OG;Wang L;Peng A
口腔癌的一线治疗通常包括手术、放射治疗，在某些情况下还包括化疗。放射和口腔肿瘤化疗药物在很大程度上通过诱导DNA损伤来产生细胞毒性，强调了细胞DNA损伤修复和反应通路在癌症治疗中的重要性。然而，肿瘤复发和获得性耐药，在治疗后的初步反应，仍然是一个主要的临床挑战。通过对同一患者原发和复发的口腔肿瘤细胞的分析，我们的研究发现PARP1在复发的肿瘤细胞中表达上调。顺铂和5-氟尿嘧啶治疗进一步增强了复发肿瘤细胞中PARP1的表达，但不能增强原发肿瘤细胞中PARP1的表达。治疗后PARP1的上调依赖于PARP和CDK7的催化活性。与已建立的PARP1在DNA修复中的功能一致，我们发现PARP1的过度表达使原代肿瘤细胞对DNA损伤治疗具有高度的抵抗力。相反，抑制PARP部分逆转了复发肿瘤细胞的治疗耐药性；PARP抑制剂和顺铂/5-氟尿嘧啶联合治疗显著敏化了体内的肿瘤反应。综上所述，我们在这里报告了PARP1上调与口腔癌复发有关的临床相关机制，并建议PARP抑制剂在口腔癌中的临床益处，目前被批准用于治疗其他几种类型的癌症。
First-line treatments for oral cancer typically include surgery, radiation, and in some cases, chemotherapy. Radiation and oral cancer chemotherapeutics confer cytotoxicity largely by inducing DNA damage, underscoring the importance of the cellular DNA damage repair and response pathways in cancer therapy. However, tumor recurrence and acquired resistance, following the initial response to treatment, remains as a major clinical challenge. By analyzing oral tumor cells derived from the primary and recurrent tumors of the same patient, our study revealed upregulated PARP1 expression in the recurrent tumor cells. Cisplatin and 5-fluorouracil treatment further augmented PARP1 expression in the recurrent, but not the primary, tumor cells. Post-treatment upregulation of PARP1 was dependent on the catalytic activities of PARP and CDK7. Consistent with the established function of PARP1 in DNA repair, we showed that overexpression of PARP1 rendered the primary tumor cells highly resistant to DNA damage treatment. Conversely, PARP inhibition partially reversed the treatment resistance in the recurrent tumor cells; combinatorial treatment using a PARP inhibitor and cisplatin/5-fluorouracil significantly sensitized the tumor response in vivo. Taken together, we reported here PARP1 upregulation as a clinically relevant mechanism involved in oral cancer recurrence, and suggested the clinical benefit of PARP inhibitors, currently approved for the treatment of several other types of cancer, in oral cancer.
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影响因子：
5.2
作者：
Wang, Feifei;Wang, Ling;Peng, Aimin
通讯作者：
Peng, Aimin
影响因子：
--
作者：
Luong KV;Wang L;Roberts BJ;Wahl JK 3rd;Peng A
通讯作者：
Peng A
双管枪：PARP抑制剂与常规化疗的组合。
影响因子：
13.5
作者：
Lu Y;Liu Y;Pang Y;Pacak K;Yang C
通讯作者：
Yang C
DOI：
10.1038/nrm.2017.53
发表时间：
2017-10
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Ray Chaudhuri A;Nussenzweig A
通讯作者：
Nussenzweig A
DOI：
10.1007/s12032-017-1057-4
发表时间：
2017-11-15
期刊：
Medical oncology (Northwood, London, England)
影响因子：
--
作者：
Dylawerska A;Barczak W;Wegner A;Golusinski W;Suchorska WM
通讯作者：
Suchorska WM