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 Bcl-2-like antiapoptotic protein, plays a role in cell immortalization and chemoresistance in a number of human malignancies. A peptidyl-prolyl cis/trans isomerase, Pin1 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 Pin1 induces apoptosis, and that Erk phosphorylates and up-regulates Mcl-1; however, the underlying mechanisms for the two phenomena are not clear yet. Here, we showed that Pin 1 stabilizes Mcl-1, which is required for Mcl-1 posphorylation by Erk. First, we found expression of Mcl-1 and Pin1 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 Pin1, resulting in stabilization of Mcl-1. Moreover, Pin1 is also required for the up-regulation of Mcl-1 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 Pin1 by using a SiRNA technique. In conclusion, the current report not only unravels a novel mechanism to link Erk/Pin1 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.
Ding
Qingqing
Q
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Huo
Longfei
L
Yang
Jer-Yen
JY
Xia
Weiya
W
Wei
Yongkun
Y
Liao
Yong
Y
Chang
Chun-Ju
CJ
Yang
Yan
Y
Lai
Chien-Chen
CC
Lee
Dung-Fang
DF
Yen
Chia-Jui
CJ
Chen
Yun-Ju Rita
YJ
Hsu
Jung-Mao
JM
Kuo
Hsu-Ping
HP
Lin
Chun-Yi
CY
Tsai
Fuu-Jen
FJ
Li
Long-Yuan
LY
Tsai
Chang-Hai
CH
Hung
Mien-Chie
MC
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006801:Humans; D020935:MAP Kinase Signaling System; D016297:Mutagenesis, Site-Directed; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009536:Niacinamide / Q000031:analogs & derivatives; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D010671:Phenylurea Compounds; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology*; D000077157:Sorafenib
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D010671:Phenylurea Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase