Ameliorating cancer cachexia by inhibiting cancer cell release of Hsp70 and Hsp90 with omeprazole

Abstract

Background: Cancer cachexia, characterized by muscle and fat tissue wasting, is a major determinant of cancer-related mortality without established treatment. Recent animal data revealed that cancer cells induce muscle wasting by releasing Hsp70 and Hsp90 as surface proteins on extracellular vesicles (EVs). Here, we test a therapeutic strategy for ameliorating cancer cachexia by inhibiting the release of Hsp70 and Hsp90 using proton pump inhibitor omeprazole.

Methods: Omeprazole effect on Hsp70/90 release through EVs by Lewis lung carcinoma (LLC) cells in vitro, serum levels of Hsp70/90 and Hsp70/90-carrying EVs in LLC tumour-bearing mice, and LLC-induced muscle protein degradation pathways in C2C12 myotubes and mice were determined. Omeprazole effect on endolysosomal pH and Rab27b expression in LLC cells were analysed.

Results: Omeprazole treatment of LLC cells inhibited Hsp70/90 and Hsp70/90-carrying EV release in a dose-dependent manner (1 to 10 μM) and attenuated the catabolic activity of LLC cell-conditioned medium on C2C12 myotubes. Systemic omeprazole administration to LLC tumour-bearing mice (5 mg/kg/day subcutaneously) for 2 weeks blocked elevation of serum Hsp70, Hsp90, and Hsp70/90-carrying EVs, abrogated skeletal muscle catabolism, and prevented loss of muscle function as well as muscle and epididymal fat mass without altering tumour growth. Consequently, median survival increased by 23.3%. Mechanistically, omeprazole increased cancer cell endolysosomal pH level dose-dependently (0.1 to 1 μM) by inhibiting vacuolar H⁺ -ATPase. Further, omeprazole suppressed the highly elevated expression of Rab27b, a key regulator of EV release, in LLC cells.

Conclusions: Omeprazole ameliorates cancer cachexia by inhibiting cancer cell release of Hsp70 and Hsp90.

Keywords: Fat tissue wasting; Hsp70; Hsp90; Lewis lung carcinoma; Muscle wasting; Rab27b; Vacuolar H+-ATPase.