Hemodynamic shear stress induces protective autophagy in HeLa cells through lipid raft-mediated mechanotransduction

Abstract

During metastatic dissemination, cancer cells experience shear stresses in narrow confinements of in vivo vasculature. Such stresses are currently known to influence a gamut of cellular processes. While a host of cells emanating from a primary tumor perish in circulation due to shear, some cells manage to migrate to distant niches and form secondary tumors. Current research focuses on how cancer cells avert such mechanical stresses and adapt themselves in order to survive. This study deals with the autophagic response of cervical cancer cells HeLa and its subline HeLa 229, exposed to physiological shear stresses in vitro, and evaluates its role as a pro-survival mechanism. It also delineates the probable mechanotransduction pathway that is involved in eliciting the stress-adaptive response in cervical cancer cells. Our results show that shear stress of physiological regime elicits protective autophagy in cervical cancer cells as an immediate response and inhibiting the same, leads to early onset of apoptosis. An effort to study the underlying mechanotransduction revealed that autophagy induction by shear stress requires intact lipid rafts which serve as signalling platforms to trigger phosphorylation of p38 mitogen activated protein kinases, leading to autophagy. This study thus gives novel insights into the mechanobiology of cervical cancer and hints at promising therapeutic targets in metastasis, the major cause of cancer mortality.

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