Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada.
Pigment Cell Melanoma Res. 2010 Jun;23(3):430-40. doi: 10.1111/j.1755-148X.2010.00698.x. Epub 2010 Mar 22.
The mitogen-activated protein kinase (MAPK) pathway is constitutively activated in the majority of melanomas, promoting cell survival, proliferation and migration. In addition, anti-apoptotic Bcl-2 family proteins Mcl-1, Bcl-xL and Bcl-2 are frequently overexpressed, contributing to melanoma's well-documented chemoresistance. Recently, it was reported that the combination of MAPK pathway inhibition by specific MEK inhibitors and Bcl-2 family inhibition by BH3-mimetic ABT-737 synergistically induces apoptotic cell death in melanoma cell lines. Here we provide the first evidence that inhibition of another key MAPK, p38, synergistically induces apoptosis in melanoma cells in combination with ABT-737. We also provide novel mechanistic data demonstrating that inhibition of p38 increases expression of pro-apoptotic Bcl-2 protein PUMA. Furthermore, we demonstrate that PUMA can be cleaved by a caspase-dependent mechanism during apoptosis and identify what appears to be the PUMA cleavage product. Thus, our findings suggest that the combination of ABT-737 and inhibition of p38 is a promising, new treatment strategy that acts through a novel PUMA-dependent mechanism.
丝裂原活化蛋白激酶（MAPK）通路在大多数黑色素瘤中持续激活，促进细胞存活、增殖和迁移。此外，抗凋亡 Bcl-2 家族蛋白 Mcl-1、Bcl-xL 和 Bcl-2 经常过表达，导致黑色素瘤具有良好记录的化疗耐药性。最近，有报道称，通过特异性 MEK 抑制剂抑制 MAPK 通路和通过 BH3 模拟物 ABT-737 抑制 Bcl-2 家族协同诱导黑色素瘤细胞系的凋亡性细胞死亡。在这里，我们首次提供证据表明，抑制另一个关键的 MAPK（p38）与 ABT-737 联合使用可协同诱导黑色素瘤细胞凋亡。我们还提供了新的机制数据，证明抑制 p38 可增加促凋亡 Bcl-2 蛋白 PUMA 的表达。此外，我们证明在凋亡过程中 PUMA 可通过依赖半胱天冬酶的机制被切割，并鉴定出似乎是 PUMA 切割产物。因此，我们的研究结果表明，ABT-737 与 p38 抑制的联合使用是一种很有前途的新治疗策略，其通过一种新的 PUMA 依赖性机制发挥作用。
