Fig. 10

a In tumor cells expressing ERβ (MDA-MB-231, MCF-7), γ- and δ-T3 bind to and activate the ERβ receptor, inducing the expression of pro-apoptotic genes such as MIC-1, EGR-1, and cathepsin-D, finally triggering apoptosis. More details about this mechanism are described in (6). Also in these cell types, a contribution by pro-apoptotic signals originating from EndoR is not to be excluded. b In tumor cells not expressing any of the canonical forms of ERs (ERα and ERβ), γ- and δ-T3 induce EndoR stress activating Ca²⁺ release in the cytoplasm. Overall, the treatment with specific forms of T3, but not α-TOC, is associated with specific Ca-dependent signals involved in the unfolded protein response (UPR), the core pathway to cope with EndoR stress in eukaryotic cells. In particular, Ca²⁺ release is followed by the activation of IRE-1, which in turn activates XBP-1 splicing, the binding of this latter to DNA, and the subsequent induction of the expression of pro-apoptotic genes. The expression of other genes associated with EndoR stress (PERK and ATF-6) is not significantly affected by T3. Our data also provide ground to speculate about the presence of a putative (orphan) receptor, possibly located at the level of the cellular membrane able to bind T3 and other estrogen mimetics such as ICI-182,730. This mechanism could be active in several cell types, independently of the presence of functional ERs