Research Papers:
SRC mediates cell cycle regulatory function of Pin1 and is a rational target in treating mucinous ovarian cancer
Elisabeth Baron1,7,*, Shubai Liu1,*, Yuanyuan Hua2,1, Junzheng Yang1, Pui-Wah Choi1, Wing-Chung Ng1, Shu-Kay Ng3, Jinyan Du4, Charlene C. Ng5, Xiao Zhen Zhou6, Kun Ping Lu6, William R. Welch5, Christopher P. Crum5, Ross S. Berkowitz1 and Shu-Wing Ng1
1 Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, Boston, Massachusetts, USA
2 Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, PR China
3 School of Medicine and Menzies Health Institute Queensland, Griffith University, Nathan, Australia
4 Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
5 Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
6 Department of Medicine, Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
7 Mount Sinai West, New York, New York, USA
* These authors contributed equally to this work
Correspondence to:
| Shu-Wing Ng, | email: | [email protected] |
Keywords: cell cycle regulation; drug sensitivity; ovarian cancer; signal transduction; combination treatment
Received: June 04, 2019 Accepted: August 16, 2019 Published: PUBLISHED_DATE
ABSTRACT
The expression of human proplyl isomerase Pin1 that controls numerous growth and cancer-driving signaling pathways was elevated in the majority of ovarian tumors. Ectopic expression of Pin1 in normal human ovarian surface epithelial cells promoted cell proliferation and phospho-tyrosine kinase profiling identified significant up-regulation of SRC phosphorylation. On the other hand, knockdown of Pin1 expression in most ovarian cancer cells resulted in slower cell growth, reduction of SRC phosphorylation, and G1 cell cycle arrest. Transient siRNA transfection to suppress SRC expression in wild-type cancer cells phenocopied the cell cycle defects of Pin1-knockdown cancer cells. However, mucinous ovarian cancer cell lines showed upregulation of SRC phosphorylation and absence of cell cycle arrest after Pin1 knockdown. The effects of SRC phosphorylation affect the cell sensitivity to Pin1 inhibitor Juglone. Mucinous ovarian cancer cells had IC50 values 2.4- to five-fold higher than other cancer cell types and required SRC inhibitor in combination with Juglone for rapid cell death. This novel node downstream of Pin1 cell cycle regulatory pathway will have significant implication for tumor type-specific treatment of ovarian cancer with Pin1 overexpression.