HIPK2-A therapeutical target to be (re)activated for tumor suppression Role in p53 activation and HIF-1α inhibition
HIPK2-A therapeutical target to be (re)activated for tumor suppression Role in p53 activation and HIF-1α inhibition
复制标题
DOI：
10.4161/cc.9.7.11125
复制
发表时间：
2010-04-01
期刊：
影响因子：
4.3
通讯作者：
D'Orazi, Gabriella
中科院分区：
文献类型：
--
作者：
Nardinocchi, Lavinia;Puca, Rosa;D'Orazi, Gabriella
抑癌基因p53通常通过突变或调节蛋白的失调而失活。这些包括同源结构域相互作用蛋白激酶2（HIPK 2），其通过在Ser 46处磷酸化p53来调节p53对DNA损伤的反应，从而诱导促凋亡转录。有令人信服的证据表明，HIPK 2也参与对缺氧的反应，作为缺氧诱导因子1 α（HIF-1 α）的共抑制因子，HIF-1 α是癌症进展中的一个主要因素，激活参与血管生成、葡萄糖代谢和侵袭的基因的转录。因此，诱导HIPK 2失调的条件将以多因素反应结束，一方面通过影响p53活性导致肿瘤化学抗性，另一方面通过影响HIF-1活性导致血管生成和细胞增殖。由于这些原因，HIPK 2蛋白是一个有前途的抗癌治疗靶点。缺氧可抑制HIPK 2的表达。在这方面，我们最近表明，缺氧驱动的HIPK 2下调不是不可逆的。我们发现，锌补充剂重新激活缺氧抑制HIPK 2，导致HIF-1通路的抑制和p53 Ser 46凋亡活性的恢复。在这里，我们讨论了这些发现和补锌与癌症治疗中化疗的潜在相关性。根据最近的研究结果，结果也将进行讨论，这些研究结果表明，用抗血管生成剂治疗癌症可能导致缺氧和选择具有增加的肿瘤侵袭性和转移的癌细胞。
Oncosuppressor p53 is often inactivated by either mutations or deregulation of regulatory proteins. These include the homeodomain-interacting protein kinase 2 (HIPK2) that, by phosphorylating p53 at Ser46 modulates p53 response to DNA damage by inducing pro-apoptotic transcription. There is compelling evidence that HIPK2 is also involved in the response to hypoxia by acting as co-suppressor of hypoxia inducible factor 1 alpha (HIF-1 alpha), a major factor in cancer progression that activates the transcription of genes involved in angiogenesis, glucose metabolism and invasion. Hence conditions that induce HIPK2 deregulation would end up in a multifactorial response leading to tumor chemoresistance by affecting p53 activity on one hand and to angiogenesis and cell proliferation by affecting HIF-1 activity on the other hand. For these reasons, HIPK2 protein is a promising target for anti-cancer therapies. HIPK2 can be inhibited by hypoxia. In this respect, we have recently shown that hypoxia-driven HIPK2 downregulation is not irreversible. We found that, zinc supplementation reactivates the hypoxia-inhibited HIPK2, leading to repression of the HIF-1 pathway and restoration of p53Ser46 apoptotic activity. Here, we discuss about these findings and the potential relevance of zinc supplementation to chemotherapy in cancer treatment. The results will be also discussed in light of recent findings showing that cancer treatment with anti-angiogenic agents may result in hypoxia and selection of cancer cells with increased tumor aggressiveness and metastasis.