Premium
Selective concomitant inhibition of mTORC1 and mTORC2 activity in estrogen receptor negative breast cancer cells by BN107 and oleanolic acid
Author(s) -
Chu Ruth,
Zhao Xiaoyue,
Griffin Chandi,
Staub Richard E.,
Shoemaker Mark,
Climent Joan,
Leitman Dale,
Cohen Isaac,
Shtivelman Emma,
Fong Sylvia
Publication year - 2010
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.25116
Subject(s) - mtorc1 , estrogen receptor , mtorc2 , pi3k/akt/mtor pathway , cancer research , apoptosis , biology , signal transduction , breast cancer , cancer , chemistry , pharmacology , microbiology and biotechnology , medicine , biochemistry
Abstract Hormonal, targeted and chemotherapeutic strategies largely depend on the expression of their cognate receptors and are often accompanied by intolerable toxicities. Effective and less toxic therapies for estrogen receptor negative (ER−) breast cancers are urgently needed. Here, we present the potential molecular mechanisms mediating the selective pro‐apoptotic effect induced by BN107 and its principle terpene, oleanolic acid (OA), on ER− breast cancer cells. A panel of breast cancer cell lines was examined and the most significant cytotoxic effect was observed in ER− breast lines. Apoptosis was the major cellular pathway mediating the cytotoxicity of BN107. We demonstrated that sensitivity to BN107 was correlated to the status of ERα. Specifically, the presence of functional ERα protected cells from BN107‐induced apoptosis and absence of ERα increased the sensitivity. BN107, an extract rich in OA derivatives, caused rapid alterations in cholesterol homeostasis, presumably by depleting cholesterol in lipid rafts (LRs), which subsequently interfered with signaling mediated by LRs. We showed that BN107 or OA treatment in ER− breast cancer cells resulted in rapid and specific inhibition of LR‐mediated survival signaling, namely mTORC1 and mTORC2 activities, by decreasing the levels of the mTOR/FRAP1, RAPTOR and RICTOR. Cotreatment with cholesterol abolished the proapoptotic effect and restored the disrupted mTOR activities. This is the first report demonstrating possible concomitant inhibition of both mTORC1 and mTORC2 activities by modulating the levels of protein constituents present in these signaling complexes, and thus provides a basis for future development of OA‐based mTOR inhibitors.