SRC-3 inhibition blocks tumor growth of pancreatic ductal adenocarcinoma

Xianzhou Song; Hui Chen; Chengwei Zhang; Yang Yu; Zhongyuan Chen; Han Liang; George Van Buren 2nd; Amy L McElhany; William E Fisher; David M Lonard; Bert W O'Malley; Jin Wang

doi:10.1016/j.canlet.2018.11.012

SRC-3 inhibition blocks tumor growth of pancreatic ductal adenocarcinoma

Cancer Lett. 2019 Feb 1:442:310-319. doi: 10.1016/j.canlet.2018.11.012. Epub 2018 Nov 10.

Authors

Xianzhou Song¹, Hui Chen¹, Chengwei Zhang¹, Yang Yu², Zhongyuan Chen³, Han Liang⁴, George Van Buren 2nd⁵, Amy L McElhany⁵, William E Fisher⁵, David M Lonard⁶, Bert W O'Malley⁷, Jin Wang⁸

Affiliations

¹ Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
² Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
³ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA; Department of Statistics, Rice University, Houston, TX, 77030, USA.
⁴ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
⁵ Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, 77030, USA.
⁶ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. Electronic address: dlonard@bcm.edu.
⁷ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. Electronic address: berto@bcm.edu.
⁸ Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX, 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. Electronic address: wangj@bcm.edu.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant and lethal disease with few treatment options. Steroid receptor coactivator-3 (SRC-3, also known as NCOA3, AIB1, pCIP, ACTR, RAC3, TRAM1) sits at the nexus of many growth signaling pathways and has been pursued as a therapeutic target for breast, prostate and lung cancers. In this study, we find that SRC-3 is overexpressed in PDAC and inversely correlates with patient overall survival. Knockdown of SRC-3 reduces pancreatic cancer cell proliferation, migration and invasion in vitro. Additionally, inhibition of SRC-3 using either shRNA or a small molecule inhibitor can significantly inhibit tumor growth in orthotopic pancreatic cancer mouse models. Collectively, this study establishes SRC-3 as a promising therapeutic target for pancreatic cancer treatment.

Keywords: Pancreatic ductal adenocarcinoma; Small molecule inhibitor; Steroid receptor coactivator.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Carcinoma, Pancreatic Ductal / genetics
Carcinoma, Pancreatic Ductal / metabolism
Carcinoma, Pancreatic Ductal / pathology
Carcinoma, Pancreatic Ductal / therapy*
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects*
Female
Gene Expression Regulation, Neoplastic
Humans
Mice, Nude
Mice, SCID
Neoplasm Invasiveness
Nuclear Receptor Coactivator 3 / antagonists & inhibitors*
Nuclear Receptor Coactivator 3 / genetics*
Nuclear Receptor Coactivator 3 / metabolism
Pancreatic Neoplasms / genetics
Pancreatic Neoplasms / metabolism
Pancreatic Neoplasms / pathology
Pancreatic Neoplasms / therapy*
RNA, Small Interfering / genetics*
RNA, Small Interfering / metabolism
RNAi Therapeutics*
Signal Transduction
Tumor Burden / drug effects
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
RNA, Small Interfering
NCOA3 protein, human
Nuclear Receptor Coactivator 3

Abstract

Publication types

MeSH terms

Substances

Grants and funding