Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Exp Cell Res. 2010 Dec 10;316(20):3387-96. doi: 10.1016/j.yexcr.2010.06.007. Epub 2010 Jun 15.
Protein phosphatase 2A (PP2A), in its activated form as a phosphatase, is a tumour suppressor. However, when PP2A is phosphorylated at the tyrosine residue (pY307), it loses its phosphatase activity and becomes inactivated. In our previous study, we found a higher expression of pY307-PP2A in HER-2/neu positive breast tumour samples and significantly correlated to tumour progression, and in this context, it could function as a proto-oncogene. The above and subsequent findings led us to postulate that the critical role of PP2A in maintaining the balance between cell survival and cell death may be linked to its phosphorylation status at its Y307 residue. Hence, we further investigated the effects of knocking down the PP2A catalytic subunit which contains the Y307 amino acid residue in two HER-2/neu positive breast cancer cell lines, BT474 and SKBR3. We showed that this causes the silenced HER-2/neu breast cancer cells to undergo apoptosis and furthermore, that such apoptosis is mediated by p38 MAPK-caspase 3/PARP activation. Understanding the role of PP2A in HER2/neu positive cells might thus provide insight into new targets for breast cancer therapy.
蛋白磷酸酶 2A（PP2A）作为一种磷酸酶，在其激活形式下是一种肿瘤抑制因子。然而，当 PP2A 在酪氨酸残基（pY307）处被磷酸化时，它会失去其磷酸酶活性并失活。在我们之前的研究中，我们发现 HER-2/neu 阳性乳腺癌样本中 pY307-PP2A 的表达更高，并与肿瘤进展显著相关，在这种情况下，它可以作为原癌基因发挥作用。上述和后续的发现使我们推测，PP2A 在维持细胞存活和细胞死亡之间平衡方面的关键作用可能与其 Y307 残基的磷酸化状态有关。因此，我们进一步研究了敲低含有 Y307 氨基酸残基的 PP2A 催化亚基对两种 HER-2/neu 阳性乳腺癌细胞系 BT474 和 SKBR3 的影响。我们表明，这会导致沉默的 HER-2/neu 阳性乳腺癌细胞发生细胞凋亡，并且这种细胞凋亡是由 p38 MAPK-caspase 3/PARP 激活介导的。因此，了解 PP2A 在 HER2/neu 阳性细胞中的作用可能为乳腺癌治疗提供新的靶点。
