Restoration of secreted frizzled-related protein 1 suppresses growth and increases cisplatin sensitivity in laryngeal carcinoma cells by downregulating NHE1.

It has been documented that secreted frizzled-related protein 1 (SFRP1) is epigenetically silenced in laryngeal carcinoma. However, the function of SFRP1 in laryngeal carcinoma remains elusive. In this study, we performed gain-of-function studies to determine the roles of SFRP1 in laryngeal carcinoma growth, tumorigenesis, and cisplatin resistance. Laryngeal carcinoma cell lines were treated with 5-aza-2'-deoxycytidine (5-aza-dC) and examined for SFRP1 expression. The effects of overexpression of SFRP1 on cell proliferation, colony formation, apoptosis, tumorigenesis, and cisplatin sensitivity were assessed. It was found that 5-aza-dC exposure significantly induced the expression of SFRP1 in both Hep-2 and SNU899 laryngeal carcinoma cells. Ectopic expression of SFRP1 significantly decreased cell proliferation and colony formation in vitro and retarded xenograft tumor growth in vivo. SFRP1-overexpressing Hep-2 cells displayed a higher percentage of apoptosis and enhancement of caspase-3 cleavage, which was coupled with loss of Δψm and increased release of cytochrome c from the mitochondria to the cytosol. Moreover, SFRP1 overexpression sensitized laryngeal carcinoma cells to cisplatin and decreased intracellular pH values. Mechanistically, SFRP1 inhibited the expression of Na+/H+ exchanger 1 (NHE1) and overexpression of NHE1 reversed the suppressive activity of SFRP1 on laryngeal carcinoma cells. In conclusion, we demonstrate that SFRP1 induces mitochondrial apoptosis and increases cisplatin sensitivity in laryngeal carcinoma cells via downregulation of NHE1. Delivery of SFRP1 may offer therapeutic benefits in the treatment of laryngeal carcinoma.