Selective killing of transformed cells by mechanical stretch

Abstract

Cancer cells differ from normal cells in several important features like anchorage independence, Warburg effect and mechanosensing. Further, in recent studies, they respond aberrantly to external mechanical distortion. Consistent with altered mechano-responsiveness, we find that cyclic stretching of tumor cells from many different tissues reduces growth rate and causes apoptosis on soft surfaces. Surprisingly, normal cells behave similarly when transformed by depletion of the rigidity sensor protein (Tropomyosin 2.1). Restoration of rigidity sensing in tumor cells promotes rigidity dependent mechanical behavior, i.e. cyclic stretching enhances growth and reduces apoptosis on soft surfaces. The mechanism of mechanical apoptosis (mechanoptosis) of transformed cells involves calcium influx through the mechanosensitive channel, Piezo1 that activates calpain 2 dependent apoptosis through the BAX molecule and subsequent mitochondrial activation of caspase 3 on both fibronetin and collagen matrices. Thus, it is possible to selectively kill tumor cells by mechanical perturbations, while stimulating the growth of normal cells.

Keywords: Apoptosis; Calpain; Cell stretching; Malignant transformation; Mechanical force; piezo1.