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Nuclear factor erythroid 2 (NF‐E2) p45‐related factor 2 interferes with homeodomain‐interacting protein kinase 2/p53 activity to impair solid tumors chemosensitivity
IUBMB Life ( IF 3.7 ) Pub Date : 2020-06-27 , DOI: 10.1002/iub.2334
Gabriella D'Orazi 1 , Alessia Garufi 1, 2 , Mara Cirone 3, 4
Affiliation  

Resistance to chemotherapy represents a major hurdle to successful cancer treatment. A key role for efficient response to anticancer therapies is played by TP53 oncosuppressor gene that indeed is mutated in 50% of human cancers or inactivated at protein level in the remaining 50%. Homeodomain‐interacting protein kinase 2 (HIPK2) is the wild‐type p53 (wtp53) apoptotic activator, and its inhibition by hypoxia or hyperglycemia may contribute to tumor chemoresistance mainly by impairing p53 apoptotic activity. Another important molecule able to induce chemoresistance is nuclear factor erythroid 2 (NF‐E2) p45‐related factor 2 (NRF2) transcription factor, whose activation by oxidative and/or electrophilic stress regulates a transcriptional antioxidant program allowing cancer cells to adapt and survive to stresses. NRF2 may shift from cytoprotective to tumor‐promoting function, according to tumor phases. NRF2 may crosstalk with both wtp53 and mutant p53 (mutp53), inhibiting the wtp53 apoptotic function and strengthening the mutp53 oncogenic function. NRF2 has also been shown to induce HIPK2 mRNA expression cooperating in inducing cytoprotection. Although HIPK2, p53, and NRF2 have been individually extensively studied, their interplay has not been clearly addressed yet. On the basis of the background and our results, we aim at hypothesizing the unexpected pro‐survival activity played by the NRF2/HIPK2/p53 interplay that can be hijacked by cancer cells to bypass drugs cytotoxicity.

中文翻译:

核因子类红细胞 2 (NF-E2) p45 相关因子 2 干扰同源域相互作用蛋白激酶 2/p53 活性以损害实体瘤的化学敏感性

对化疗的抵抗是成功治疗癌症的主要障碍。TP53 抑癌基因确实在 50% 的人类癌症中发生突变,或者在其余 50% 的癌症中在蛋白质水平上失活,因此对抗癌疗法的有效反应起着关键作用。同源域相互作用蛋白激酶 2 (HIPK2) 是野生型 p53 (wtp53) 凋亡激活剂,其通过缺氧或高血糖抑制可能主要通过削弱 p53 凋亡活性而导致肿瘤化学抗性。另一个能够诱导化学抗性的重要分子是核因子类红细胞 2 (NF-E2) p45 相关因子 2 (NRF2) 转录因子,其通过氧化和/或亲电应激激活调节转录抗氧化程序,使癌细胞适应并存活压力。根据肿瘤阶段,NRF2 可能从细胞保护功能转变为肿瘤促进功能。NRF2 可能与 wtp53 和突变型 p53 (mutp53) 发生串扰,抑制 wtp53 的凋亡功能并加强 mutp53 的致癌功能。NRF2 还显示出诱导 HIPK2 mRNA 表达,协同诱导细胞保护。尽管 HIPK2、p53 和 NRF2 已分别进行了广泛的研究,但它们的相互作用尚未得到明确解决。基于背景和我们的结果,我们的目标是假设 NRF2/HIPK2/p53 相互作用会产生意想不到的促生存活性,癌细胞可以劫持这种活性来绕过药物的细胞毒性。抑制 wtp53 凋亡功能并增强 mutp53 致癌功能。NRF2 还显示出诱导 HIPK2 mRNA 表达,协同诱导细胞保护。尽管 HIPK2、p53 和 NRF2 已分别进行了广泛的研究,但它们的相互作用尚未得到明确解决。基于背景和我们的结果,我们的目标是假设 NRF2/HIPK2/p53 相互作用会产生意想不到的促生存活性,癌细胞可以劫持这种活性来绕过药物的细胞毒性。抑制 wtp53 凋亡功能并增强 mutp53 致癌功能。NRF2 还显示出诱导 HIPK2 mRNA 表达,协同诱导细胞保护。尽管 HIPK2、p53 和 NRF2 已分别进行了广泛的研究,但它们的相互作用尚未得到明确解决。基于背景和我们的结果,我们的目标是假设 NRF2/HIPK2/p53 相互作用会产生意想不到的促生存活性,癌细胞可以劫持这种活性来绕过药物的细胞毒性。
更新日期:2020-06-27
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