NSAID Sulindac and Its Analog Bind RXRα and Inhibit RXRα-Dependent AKT Signaling

Abstract

SUMMARY Non-steroidal anti-inflammatory drugs (NSAIDs) exert their anti-cancer effects through cyclooxygenase-2 (COX-2)-dependent and -independent mechanisms. Here we report that Sulindac, an NSAID, induces apoptosis by binding to retinoid X receptor-α (RXRα). We identified an N-terminally-truncated RXRα (tRXRα) in several cancer cell lines and primary tumors, which interacted with the p85α subunit of phosphatidylinositol-3-OH kinase (PI3K). Tumor necrosis factor-α (TNFα) promoted tRXRα interaction with the p85α, activating PI3K/AKT signaling. When combined with TNFα, Sulindac inhibited TNFα-induced tRXRα/p85α interaction, leading to activation of the death receptor-mediated apoptotic pathway. We designed and synthesized a Sulindac analog K-80003, which has increased affinity to RXRα but lacks COX inhibitory activity. K-80003 displayed enhanced efficacy in inhibiting tRXRα-dependent AKT activation and tRXRα tumor growth in animals.

Retinoid X receptors: common heterodimerization partners with distinct functions

“…Indeed, mouse and human obese visceral fat overexpress the ubiquitin hydrolase/ligase UCH-L1, which catalyzes, by a yet undefined molecular mechanism, RXRα ubiquitinylation and breakdown 45 . Quite similarly, RXRα is downregulated in many cancer cells and tissues and proteolytically degraded by cathepsin L and/or calpain, generating a cytoplasmic, N-terminally 44 kDa truncated receptor able to interact with the protein kinase Akt and to activate the PI3K/Akt signalling pathway 46 . Interestingly, this 44kDa truncated RXR has also been located in the mitochondrial matrix in which it exerts a transcriptional activity 47,48 , suggesting that RXR can shuttle between the cytoplasmic and nuclear compartments.…”

“…RXRs can bind a variety of natural and synthetic derivatives, ranging from ω-3 unsaturated fatty acids, the non steroidal anti-inflammatory drug sulindac to organotins 46,91 . A number of RXR agonists with no isotype selectivity have been synthesized, and much like for other NRs, the concept of selective nuclear receptor modulator (SNuRM) applies to this class of compounds.…”

Pharmacological protection of retinal pigmented epithelial cells by sulindac involves PPAR-α

“…The finding that sulindac's protective effect may involve activation of PPAR-α could be related to the known ability of PPARs to complex with RXRs (11). In this regard, sulindac has previously been reported to induce apoptosis in an embryonic carcinoma cell line (F9) by binding to a truncated form of the retinoid-X-receptor-α (RXRα) (10).…”

“…Sulindac has also been shown to be an inhibitor of phosphodiesterase type 5 (PDE5) (9) and has been reported to react with both the peroxisome proliferator activator receptors (PPARs) and a truncated retinoic acid receptor (RXR) (10). The members of the PPAR nuclear receptor family are involved in certain key protective pathways in a variety of cell types and are known to complex with the RXR family (11).…”

Oxazole and Thiazole Analogs of Sulindac for Cancer Prevention

“…sulindac benzylamine inhibits cyclic-GMP phosphodiesterase isozyme PDE5 and activates cGMP-dependent protein kinase G at concentrations that suppress colon tumor cell growth, while it has no COX-related activity. An example of a 4-substituted analog of sulindac sulfide lacking cyclooxygenase activity is K-80003 [34]. This analog contains 4-isopropyl substituted benzylidine and shows increased affinity to retinoid X receptor-α compared with sulindac sulfide, but is not active against COXs.…”