Small molecule inhibition of the steroid receptor coactivators, SRC-3 and SRC-1.

Abstract

Overexpression of steroid receptor coactivator (SRC)-1 and SRC-3 is associated with cancer initiation, metastasis, advanced disease, and resistance to chemotherapy. In most of these cases, SRC-1 and SRC-3 have been shown to promote tumor cell growth by activating nuclear receptor and multiple growth factor signaling cascades that lead to uncontrolled tumor cell growth. Up until now, most targeted chemotherapeutic drugs have been designed largely to block a single pathway at a time, but cancers frequently acquire resistance by switching to alternative growth factor pathways. We reason that the development of chemotherapeutic agents against SRC coactivators that sit at the nexus of multiple cell growth signaling networks and transcriptional factors should be particularly effective therapeutics. To substantiate this hypothesis, we report the discovery of 2,2'-bis-(Formyl-1,6,7-trihydroxy-5-isopropyl-3-methylnaphthalene (gossypol) as a small molecule inhibitor of coactivator SRC-1 and SRC-3. Our data indicate that gossypol binds directly to SRC-3 in its receptor interacting domain. In MCF-7 breast cancer cells, gossypol selectively reduces the cellular protein concentrations of SRC-1 and SRC-3 without generally altering overall protein expression patterns, SRC-2, or other coactivators, such as p300 and coactivator-associated arginine methyltransferase 1. Gossypol reduces the concentration of SRC-3 in prostate, lung, and liver cancer cell lines. Gossypol inhibits cell viability in the same cancer cell lines where it promotes SRC-3 down-regulation. Additionally, gossypol sensitizes lung and breast cancer cell lines to the inhibitory effects of other chemotherapeutic agents. Importantly, gossypol is selectively cytotoxic to cancer cells, whereas normal cell viability is not affected. This data establish the proof-of-principle that, as a class, SRC-1 and SRC-3 coactivators are accessible chemotherapeutic targets. Given their function as integrators of multiple cell growth signaling systems, SRC-1/SRC-3 small molecule inhibitors comprise a new class of drugs that have potential as novel chemotherapeutics able to defeat aspects of acquired cancer cell resistance mechanisms.

• Authors: Ying Wang, David M Lonard, Yang Yu, Dar-Chone Chow, Timothy G Palzkill, Bert W O'Malley
• Journal: Molecular endocrinology (Baltimore, Md.) (Mol Endocrinol) Vol. 25 Issue 12 Pg. 2041-53 (Dec 2011) ISSN: 1944-9917 [Electronic] United States
• PMID: 22053001 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• AZD 6244
• Antineoplastic Agents
• Benzimidazoles
• Estrogen Receptor alpha
• Leupeptins
• Nuclear Receptor Coactivator 2
• Proteasome Inhibitors
• NCOA1 protein, human
• NCOA3 protein, human
• Nuclear Receptor Coactivator 1
• Nuclear Receptor Coactivator 3
• MAP Kinase Kinase 1
• Proteasome Endopeptidase Complex
• Gossypol
• benzyloxycarbonylleucyl-leucyl-leucine aldehyde

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Benzimidazoles (pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Down-Regulation (drug effects)
• Drug Synergism
• Estrogen Receptor alpha (metabolism)
• Gossypol (pharmacology)
• Humans
• Inhibitory Concentration 50
• Leupeptins (pharmacology)
• MAP Kinase Kinase 1 (antagonists & inhibitors)
• Male
• Mice
• Nuclear Receptor Coactivator 1 (antagonists & inhibitors, genetics, metabolism)
• Nuclear Receptor Coactivator 2 (metabolism)
• Nuclear Receptor Coactivator 3 (antagonists & inhibitors, genetics, metabolism)
• Proteasome Endopeptidase Complex (metabolism)
• Proteasome Inhibitors
• Protein Binding
• Protein Interaction Domains and Motifs
• Protein Stability
• Transcription, Genetic