Tong Zhimin, Singh Gurmit, Rainbow Andrew J
Department of Biology, McMaster University, Hamilton, Ontario L8S 4K1, Canada.
Cancer Res. 2002 Oct 1;62(19):5528-35.
Photodynamic therapy (PDT) is a cancer therapy in which a photosensitizer selectively accumulates in tumor cells and is subsequently activated by light of a specific wavelength. The activation of the photosensitizer leads to cytotoxic photoproducts that result in tumor regression. PDT can lead to several cellular responses including cell cycle arrest, necrosis, and apoptosis, as well as trigger many signaling pathways. It has been suggested that extracellular signal-activated protein kinases (ERKs), one subfamily of mitogen-activated protein kinases, play a crucial role in the cellular response to radiation therapy and chemotherapy. However, the role of ERKs in the cell survival after PDT is less clear. We have examined the response of the extracellular signal-regulated kinase ERK1/2 in PDT-resistant (LFS087) and PDT-sensitive (GM38A) cells after Photofrin-mediated PDT. ERK1/2 activity was induced rapidly in both cell types after PDT. The PDT-induced ERK1/2 activity was transient in GM38A cells and by 3 h had returned to a level significant lower than basal levels, whereas the induction of ERK1/2 was sustained in LFS087 cells and lasted for at least 11 h. Blocking of the sustained ERK activity with PD98059, an inhibitor of mitogen-activated protein/ERK kinase, significantly decreased cell survival of LFS087 after PDT. PDT also induced the expression of mitogen-activated protein kinase phosphatase, MKP-1, but reduced Raf-1 protein levels in both cell types. In GM38A cells, the substantially induced levels of MKP-1 correlated with the transient activation of ERK1/2 by PDT, and both basal and induced levels of MKP-1 were substantially greater in GM38 compared with Li Fraumeni syndrome cells. These observations suggest that sustained ERK1/2 activation protects cells from Photofrin-mediated phototoxicity and that the duration of ERK1/2 activation is regulated by MKP-1. In addition, the activation of ERK1/2 by Photofrin-mediated PDT is Raf-1 independent.
光动力疗法（PDT）是一种癌症治疗方法，其中光敏剂选择性地在肿瘤细胞中积累，随后被特定波长的光激活。光敏剂的激活会产生细胞毒性光产物，导致肿瘤消退。PDT可引发多种细胞反应，包括细胞周期停滞、坏死和凋亡，还能触发许多信号通路。有研究表明，细胞外信号激活蛋白激酶（ERK）作为丝裂原激活蛋白激酶的一个亚家族，在细胞对放射治疗和化疗的反应中起关键作用。然而，ERK在PDT后细胞存活中的作用尚不清楚。我们研究了在Photofrin介导的PDT后，PDT耐药（LFS087）和PDT敏感（GM38A）细胞中细胞外信号调节激酶ERK1/2的反应。PDT后，两种细胞类型中的ERK1/2活性均迅速被诱导。PDT诱导的ERK1/2活性在GM38A细胞中是短暂的，到3小时时已恢复到明显低于基础水平，而在LFS087细胞中ERK1/2的诱导是持续的，持续至少11小时。用丝裂原激活蛋白/ERK激酶抑制剂PD98059阻断持续的ERK活性，可显著降低LFS087细胞在PDT后的存活率。PDT还诱导了丝裂原激活蛋白激酶磷酸酶MKP-1的表达，但两种细胞类型中的Raf-1蛋白水平均降低。在GM38A细胞中，PDT对MKP-1的大量诱导与ERK1/2的短暂激活相关，与李-弗劳梅尼综合征细胞相比，GM38细胞中MKP-1的基础水平和诱导水平均显著更高。这些观察结果表明，持续的ERK1/2激活可保护细胞免受Photofrin介导的光毒性，且ERK1/2激活的持续时间受MKP-1调节。此外，Photofrin介导的PDT对ERK1/2的激活不依赖于Raf-1。
