Intracellular targeting of STIP1 inhibits human cancer cell line growth

Abstract

Background: Extracellular and cell-surface molecules remain the most common druggable cancer targets.However, intracellular therapeutic modalities are gaining momentum. The overexpression of stress-induced phosphoprotein 1 (STIP1), an adaptor protein that coordinates the functions of different chaperones in protein folding, has been reported in several solid malignancies. Here, we investigated the effects of intracellular STIP1 inhibition, attained either through the HEPES-mediated cytosolic delivery of anti-STIP1 antibodies or the use of a cell-penetrating signal-tagged peptide 520, in different human cancer cell lines and luciferase-expressing murine ovarian cancer cells (MOSEC/Luc) tumor-bearing C57BL/6 mice. Methods:The effects of STIP1 in different human cell lines were determined by cell viability, cell cytotoxicity and cell apoptosis assays. Immunoblotting was used to assess the relevant proteins found in this study and tumor xenograft mice models were also employed.Results: Intracellular targeting of STIP1 inhibited cancer cell line growth and promoted caspase 3-dependent apoptotic cell death. Moreover, the intracellular delivery of anti-STIP1 antibodies facilitated the degradation of STIP1 and two of its client proteins, lysine-specific demethylase 1 and Janus kinase 2.In vivo studies demonstrated that survival of mice bearing experimental tumors was improved by administration of anti-STIP1 antibodies.Conclusions: Our findings demonstrate that the cytosolic inhibition of STIP1 in tumor cells is feasible and provides a solid basis for further investigation of STIP1 as an intracellular cancer target. Our findings demonstrate that cytosolic inhibition of STIP1 in tumor cells is feasible and provide a solid basis for further exploration of STIP1 as an intracellular cancer target.

Diagnostic value of the serum STIP1 concentration in patients with HCC and AFP-negative HCC

“…It is actively involved in transcription regulation, cell cycle regulation, signal transduction, protein folding, and cell division [19] . Previous studies have consistently demonstrated that elevated expression of STIP1 is commonly associated with an unfavorable prognosis in patients with various malignant tumors, including hepatocellular carcinoma, pancreatic cancer, colorectal cancer, gastric cancer, and ovarian cancer [20] . However, the diagnostic value of STIP1 in HCC and ANHC has not been reported.…”