Transcriptional activation of HIF-1 by a ROS-ERK axis underlies the resistance to photodynamic therapy.
Transcriptional activation of HIF-1 by a ROS-ERK axis underlies the resistance to photodynamic therapy.
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DOI：
10.1371/journal.pone.0177801
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Rivarola VA
中科院分区：
文献类型：
--
作者：
Lamberti MJ;Pansa MF;Vera RE;Fernández-Zapico ME;Rumie Vittar NB;Rivarola VA
光动力学疗法（PDT）是一种很有前途的癌症治疗方法，涉及通过用可见光局部照射来激活光敏剂（PS）。PS的激发导致一系列光化学反应，并因此导致有害活性氧物质（ROS）的局部产生，从而导致有限的或无系统性缺陷。然而，对这种有前途的疗法的耐药性的发展减缓了其向临床实践的转化。因此，对PDT耐药的分子机制的理解越来越有必要。在这里，我们的目的是研究是否存在PDT的结果和ROS参与光敏化癌细胞的耐药机制之间的关系。为了重现各自原始肿瘤的肿瘤结构，我们开发了一种多细胞三维球体系统，其包括围绕低氧核心的常氧外围。使用Me-ALA，PS PpIX的前药，在人结直肠球状体中，我们证明HIF-1转录活性强烈上调并介导PDT抗性表型。RNAi敲低HIF-1会损害对PDT的抗性。PDT后氧化应激介导的ERK 1/2激活参与了光动力处理后HIF-1转录活性的正向调节。ROS清除和MEK/ERK通路抑制消除PDT介导的HIF-1上调。总之，我们的数据表明，对PDT的抗性部分是由ROS-ERK 1/2-HIF-1轴的激活介导的，因此，确定了可与PDT组合使用的新的治疗靶点。
Photodynamic therapy (PDT), a promising treatment option for cancer, involves the activation of a photosensitizer (PS) by local irradiation with visible light. Excitation of the PS leads to a series of photochemical reactions and consequently the local generation of harmful reactive oxygen species (ROS) causing limited or none systemic defects. However, the development of resistance to this promising therapy has slowed down its translation into the clinical practice. Thus, there is an increase need in understanding of the molecular mechanism underlying resistance to PDT. Here, we aimed to examine whether a relationship exists between PDT outcome and ROS-involvement in the resistance mechanism in photosensitized cancer cells. In order to recapitulate tumor architecture of the respective original tumor, we developed a multicellular three-dimensional spheroid system comprising a normoxic periphery, surrounding a hypoxic core. Using Me-ALA, a prodrug of the PS PpIX, in human colorectal spheroids we demonstrate that HIF-1 transcriptional activity was strongly up-regulated and mediates PDT resistant phenotype. RNAi knockdown of HIF-1 impairs resistance to PDT. Oxidative stress-mediated activation of ERK1/2 followed PDT was involved on positive modulation of HIF-1 transcriptional activity after photodynamic treatment. ROS scavenging and MEK/ERK pathway inhibition abrogated the PDT-mediated HIF-1 upregulation. Together our data demonstrate that resistance to PDT is in part mediated by the activation of a ROS-ERK1/2-HIF-1 axis, thus, identifying novel therapeutic targets that could be used in combination with PDT.