Functions of nuclear receptors in cancer metabolism

Abstract

Deregulation of cancer metabolism is one of the biological features that drive

carcinogenesis. In this study, the roles of nuclear receptors (NRs) in nutrient and drug

metabolism in cancer cells were investigated. Studies have shown an association

between diabetes and breast cancer and here we sought to investigate the crosstalk

between estrogen and insulin signaling. Estradiol induced growth of insulin primed

MCF-7 cells but had no significant effect on unprimed MCF-7 cells. Interestingly,

although estradiol-induced growth was mediated through estrogen receptor  (ER),

the comparable expression of ER between insulin primed and unprimed cells

suggests that ER alone does not account for estradiol-induced growth and that an

additional factor may be required. The lack of estradiol growth induction in the

presence of PI3K and Erk inhibitors coupled with the estradiol-induced

phosphorylation of Akt and Erk proteins indicates a cross talk between ER signaling

and PI3K/Akt and Erk signaling pathways. Estradiol treatment induced the expression

of cyclin A and cyclin B in an ER-dependent manner, suggesting estradiol promotes xii

cell cycle progression. Finally, metformin but not thiazolidinediones, which are well

known anti-diabetic drugs, inhibited estradiol-induced growth, suggesting that

metformin treatment of breast cancer patients with diabetes would improve the

outcome of the breast cancer.

The roles of NRs in drug metabolism by determining their potential as

combinational partners with other anti-cancer drugs were also investigated. To that

end, all 48 NRs and 48 biological anti-cancer targets in six pairs of lung cell lines,

where each pair was obtained from the same patient, were profiled. Analysis of the

expression profile revealed that some NRs and anti-cancer targets had distinct

expression patterns in normal versus tumor cells and primary tumor versus metastatic

cell lines. Remarkably, the evaluation of nuclear receptor ligand TO901317 for liver

X receptor (LXR) demonstrated its combined potential with cMET inhibitor

(PHA665752) or epidermal growth factor (EGFR) inhibitor (gefitinib) in H2073 and

H1993. Mechanistically, combined treatment suppressed cell cycle progression by

inhibiting cyclin D1 and cyclin B. Taken together, this study gives possible links

between diabetes and breast cancer as well as the potential use of NR ligands in

combined therapeutics with other anti-cancer drugs