Mutation of the gene encoding the circadian clock component PERIOD2 in oncogenic cells confers chemoresistance by up-regulating the Aldh3a1 gene
Mutation of the gene encoding the circadian clock component PERIOD2 in oncogenic cells confers chemoresistance by up-regulating the Aldh3a1 gene
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DOI：
10.1074/jbc.ra118.004942
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发表时间：
2019-01-11
影响因子：
4.8
通讯作者：
Ohdo, Shigehiro
中科院分区：
文献类型：
--
作者：
Katamune, Chiharu;Koyanagi, Satoru;Ohdo, Shigehiro
昼夜节律的紊乱已被认为增加了癌症发生的风险。PER2基因编码哺乳动物生物钟的主要成分之一，在控制生理和行为的昼夜节律方面起着关键作用。PER2也被报道可以抑制细胞的恶性转化，但它在调节癌症对化疗药物的敏感性中的作用尚不清楚。在这项研究中，我们发现从PER2突变(PER2(m/m))小鼠制备的癌基因转化的胚胎成纤维细胞对常见的化疗药物具有耐药性，这种耐药性与乙醛脱氢酶3a1(Aldh3a1)基因的上调有关。共表达癌基因H-ras(V12)和SV40大T抗原可诱导WT和PER2(m/m)细胞发生恶性转化，而化疗药物甲氨蝶呤、吉西他滨、依托泊苷、长春新碱和奥沙利铂对PER2(m/m)细胞的细胞毒作用明显减轻。虽然这两个癌基因的引入增加了Aldh3a1在WT和PER2(m/m)细胞中的表达，但PER2(m/m)细胞中ALDH3A1的蛋白水平大约是WT细胞的7倍。癌基因转化的PER2(m/m)细胞中ALDH3A1水平的升高足以防止化疗药物诱导的活性氧积累。因此，shRNA介导的Aldh3a1表达抑制缓解了PER2(m/m)细胞的化疗耐药性。这些结果提示突变的PER2在多重耐药的发展中起作用，并可能为癌症管理的治疗策略提供参考。
Disruption of circadian rhythms has been implicated in an increased risk for cancer development. The Period2 (Per2) gene encodes one of the major components of the mammalian circadian clock, which plays a key role in controlling the circadian rhythms in physiology and behavior. PER2 has also been reported to suppress the malignant transformation of cells, but its role in the regulation of cancer susceptibility to chemotherapeutic drugs remains unclear. In this study, we found that oncogene-transformed embryonic fibroblasts prepared from Per2-mutant (Per2(m/m)) mice, which are susceptible to both spontaneous and radiation-induced tumorigenesis, were resistant against common chemotherapeutic drugs and that this resistance is associated with up-regulation of the aldehyde dehydrogenase 3a1 (Aldh3a1) gene. Co-expression of the oncogenes H-ras(V12) and SV40 large T-antigen induced malignant transformation of both WT and Per2(m/m) cells, but the cytotoxic effects of the chemotherapeutic agents methotrexate, gemcitabine, etoposide, vincristine, and oxaliplatin were significantly alleviated in the oncogene-transformed Per2(m/m) cells. Although introduction of the two oncogenes increased the expression of Aldh3a1 in both WT and Per2(m/m) cells, the ALDH3A1 protein levels in the Per2(m/m) cells were approximate to 7-fold higher than in WT cells. The elevated ALDH3A1 levels in the oncogene-transformed Per2(m/m) cells were sufficient to prevent chemotherapeutic drug-induced accumulation of reactive oxygen species. Consequently, shRNA-mediated suppression of Aldh3a1 expression relieved the chemoresistance of the Per2(m/m) cells. These results suggest a role for mutated PER2 in the development of multiple drug resistance and may inform therapeutic strategies for cancer management.