The sensitivity of cancer cells to pheophorbide a-based photodynamic therapy is enhanced by Nrf2 silencing.
The sensitivity of cancer cells to pheophorbide a-based photodynamic therapy is enhanced by Nrf2 silencing.
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DOI：
10.1371/journal.pone.0107158
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Kwak MK
中科院分区：
文献类型：
--
作者：
Choi BH;Ryoo IG;Kang HC;Kwak MK
光动力疗法（PDT）已成为一种有效的治疗多种实体肿瘤的方法。已知转录因子NRF2可以防止氧化和亲电应激；然而，它在癌症中的组成活性赋予了抗癌药物的抗性。在本研究中，我们通过NRF2敲除乳腺癌MDA-MB-231细胞，研究了NRF2信号作为基于Pba的PDT的潜在分子决定因素。稳定敲除NRF2的细胞在PDT后显示出增强的细胞毒性和凋亡/坏死细胞死亡，同时单线态氧和活性氧（ROS）水平升高。荧光Pba的共聚焦显微镜显示nrf2敲除细胞比对照细胞积累更多的Pba。随后对膜药物转运蛋白表达的分析表明，BCRP的基础表达依赖于nrf2。在所测量的药物转运体中，乳腺癌耐药蛋白（BCRP; ABCG2）的基础表达仅通过敲低nrf2而降低。此外，与BCRP特异性抑制剂孵育后，两种细胞系的差异细胞Pba积累和ROS被消除。此外，与对照组相比，nrf2敲低的细胞表达低水平的过氧化物还氧蛋白3，这意味着线粒体ROS防御系统的减弱可能有助于PDT致敏。在结肠癌HT29细胞中进一步证实了NRF2-BCRP通路在Pba-PDT应答中的作用。具体来说，NRF2敲低导致PDT后BCRP表达减少，细胞死亡增加，单线态氧和ROS水平增加。同样，在乳腺癌MCF-7细胞、结肠癌HCT116细胞、肾癌A498细胞和胶质母细胞瘤A172细胞中，用NRF2 shRNA处理后，pdt诱导的ROS生成显著增加。综上所述，这些结果表明NRF2的操纵可以增强多种癌细胞中Pba-PDT的敏感性。
Photodynamic therapy (PDT) has emerged as an effective treatment for various solid tumors. The transcription factor NRF2 is known to protect against oxidative and electrophilic stress; however, its constitutive activity in cancer confers resistance to anti-cancer drugs. In the present study, we investigated NRF2 signaling as a potential molecular determinant of pheophorbide a (Pba)-based PDT by using NRF2-knockdown breast carcinoma MDA-MB-231 cells. Cells with stable NRF2 knockdown showed enhanced cytotoxicity and apoptotic/necrotic cell death following PDT along with increased levels of singlet oxygen and reactive oxygen species (ROS). A confocal microscopic visualization of fluorogenic Pba demonstrated that NRF2-knockdown cells accumulate more Pba than control cells. A subsequent analysis of the expression of membrane drug transporters showed that the basal expression of BCRP is NRF2-dependent. Among measured drug transporters, the basal expression of breast cancer resistance protein (BCRP; ABCG2) was only diminished by NRF2-knockdown. Furthermore, after incubation with the BCRP specific inhibitor, differential cellular Pba accumulation and ROS in two cell lines were abolished. In addition, NRF2-knockdown cells express low level of peroxiredoxin 3 compared to the control, which implies that diminished mitochondrial ROS defense system can be contributing to PDT sensitization. The role of the NRF2-BCRP pathway in Pba-PDT response was further confirmed in colon carcinoma HT29 cells. Specifically, NRF2 knockdown resulted in enhanced cell death and increased singlet oxygen and ROS levels following PDT through the diminished expression of BCRP. Similarly, PDT-induced ROS generation was substantially increased by treatment with NRF2 shRNA in breast carcinoma MCF-7 cells, colon carcinoma HCT116 cells, renal carcinoma A498 cells, and glioblastoma A172 cells. Taken together, these results indicate that the manipulation of NRF2 can enhance Pba-PDT sensitivity in multiple cancer cells.
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影响因子：
3.8
作者：
Cho, Hye-Youn;Kleeberger, Steven R.
通讯作者：
Kleeberger, Steven R.
影响因子：
10.5
作者：
Itoh, K;Wakabayashi, N;Yamamoto, M
通讯作者：
Yamamoto, M
影响因子：
10.5
作者：
Jaramillo MC;Zhang DD
通讯作者：
Zhang DD
DOI：
10.1006/bbrc.1997.6943
发表时间：
1997-07-18
影响因子：
3.1
作者：
Itoh, K;Chiba, T;Nabeshima, Y
通讯作者：
Nabeshima, Y
影响因子：
9.7
作者：
Cho, Jeong-Min;Manandhar, Sarala;Kwak, Mi-Kyoung
通讯作者：
Kwak, Mi-Kyoung