Down-regulation of myeloid cell leukemia-1 through inhibiting Erk/Pin 1 pathway by sorafenib facilitates chemosensitization in breast cancer

Myeloid cell leukemia-1 (Mcl-1), a Bel-2-like antiapoptotic protein, plays a role in cell immortalization and chemoresistance in a number of human malignancies. A peptidylprolyl cis/trans isomerase, Pinl is involved in many cellular events, such as cell cycle progression, cell proliferation, and differentiation through isomerizing prophosphorylated substrates. It has been reported that down-regulation of Pint induces apoptosis, and that Erk phosphorylates and upregulates Mcl-1; however, the underlying mechanisms for the two phenomena are not clear yet. Here, we showed that Pin I stabilizes Mcl-1, which is required for Mcl-I posphorylation by Erk. First, we found expression of Mcl-1 and Not were positively correlated and associated with poor survival in human breast cancer. We then showed that Erk could phosphorylate Mcl-1 at two consensus residues, Thr 92 and 163, which is required for the association of Mcl-1 and Pin 1, resulting in stabilization of Mcl-I. Moreover, Not is also required for the up-regulation of Mcl-I by Erk activation. Based on this newly identified mechanism of Mcl-1 stabilization, two strategies were used to overcome Mcl-1-mediated chemoresistance: inhibiting Erk by Sorafenib, an approved clinical anticancer drug, or knocking down Pinl by using a SiRNA technique. In conclusion, the current report not only unravels a novel mechanism to link Erk/Pinl pathway and Mcl-1-mediated chemoresistance but also provides a plausible combination therapy, Taxol (Paclitaxel) plus Sorafenib, which was shown to be effective in killing breast cancer cells.