Both TWIST and the endothelin-1 (ET-1)/endothelin A receptor (ETAR) signaling are important in osteosarcoma (OS) progression. In the present study, the interaction between TWIST and ET-1/ETAR signaling in OS cells was investigated, and the impact of the functional interaction on OS cell survival against chemotherapy agent-induced apoptosis was assessed. TWIST was overexpressed and knocked down in Saos-2 and MG-63 OS cells, respectively. In Saos-2 cells, overexpression of TWIST significantly decreased ET-1 mRNA and protein expression levels, cell survival against cisplatin and phosphorylation of Akt at serine 473 (ser473), which was abolished by the selective phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, or the selective ETAR inhibitor, BQ123. In MG-63 cells, knockdown of TWIST significantly increased ET-1 expression, cell survival against cisplatin and phosphorylation of Akt at ser473. However, exogenous ET-1 only partially rescued cell survival against cisplatin-induced apoptosis in the cells in which TWIST had been knocked down in the presence of LY294002. In conclusion, we have demonstrated that TWIST significantly, although only partially, decreases OS cell survival against cisplatin by downregulating ET-1/ETAR signaling via inhibition of the PI3K/Akt pathway. To the best of our knowledge, the present study has provided the first evidence of a functional interaction between TWIST and ET-1/ETAR signaling in OS cells. This finding adds novel insights into the molecular mechanisms underlying OS progression, cell survival and chemoresistance.
Keywords: TWIST; cell survival; cisplatin; endothelin A receptor; endothelin-1; osteosarcoma.