Chemotherapy resistance and metastasis-promoting effects of thyroid hormone in hepatocarcinoma cells are mediated by suppression of FoxO1 and Bim pathway.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide, and systemic chemotherapy is the major treatment strategy for late-stage HCC patients. Poor prognosis following chemotherapy is the general outcome owing to recurrent resistance. Recent studies have suggested that in addition to cytotoxic effects on tumor cells, chemotherapy can induce an alternative cascade that supports tumor growth and metastasis. In the present investigation, we showed that thyroid hormone (TH), a potent hormone-mediating cellular differentiation and metabolism, acts as an antiapoptosis factor upon challenge of thyroid hormone receptor (TR)-expressing HCC cells with cancer therapy drugs, including cisplatin, doxorubicin and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TH/TR signaling promoted chemotherapy resistance through negatively regulating the pro-apoptotic protein, Bim, resulting in doxorubicin-induced metastasis of chemotherapy-resistant HCC cells. Ectopic expression of Bim in hepatoma cells challenged with chemotherapeutic drugs abolished TH/TR-triggered apoptosis resistance and metastasis. Furthermore, Bim expression was directly transactivated by Forkhead box protein O1 (FoxO1), which was negatively regulated by TH/TR. TH/TR suppressed FoxO1 activity through both transcriptional downregulation and nuclear exclusion of FoxO1 triggered by Akt-mediated phosphorylation. Ectopic expression of the constitutively active FoxO1 mutant, FoxO1-AAA, but not FoxO1-wt, diminished the suppressive effect of TH/TR on Bim. Our findings collectively suggest that expression of Bim is mediated by FoxO1 and indirectly downregulated by TH/TR, leading to chemotherapy resistance and doxorubicin-promoted metastasis of hepatoma cells.

Visible light-responsive core-shell structured In2O3@CaIn2O4 photocatalyst with superior bactericidal properties and biocompatibility.

Antibacterial activity of photocatalytic substrates is primarily induced by ultraviolet light irradiation. Visible light-responsive photocatalysts were recently discovered, offering greater opportunity to use photocatalysts as disinfectants in our living environment. The development of antibacterial photocatalysts, however, has mainly focused on titanium oxide (TiO(2))-related materials with antibacterial properties not comparable with conventional chemical disinfectants. This study demonstrated that a core-shell structured In(2)O(3)@CaIn(2)O(4) substrate has superior visible light-induced bactericidal properties, as compared with several commercially available and laboratory-prepared visible light-responsive photocatalysts. The high performance is enhanced by more easily photoexcited electron transfer between the interfaces of In(2)O(3) and CaIn(2)O(4) to minimize the electron-hole recombination during photocatalysis. Additionally, when compared with TiO(2)-based photocatalysts, In(2)O(3)@CaIn(2)O(4) treatments did not induce significant cell death and tissue damage, implying a superior biocompatibility. These findings suggest that In(2)O(3)@CaIn(2)O(4) may have potential application in the development of a safer and highly bactericidal photocatalyst. FROM THE CLINICAL EDITOR: A photocatalytic susbstrate is described that functions in visible light, possesses bactericidal properties and better biocompatibility than the standard TiO(2) based methods.