Brefeldin A triggers apoptosis associated with mitochondrial breach and enhances HA14-1- and anti-Fas-mediated cell killing in follicular lymphoma cells

Abstract

Follicular lymphoma (FL) remains a fatal disease of increasing worldwide incidence. Since patients with FL eventually develop resistance to conventional anticancer agents, and due to BCL-2 overexpression present with profoundly compromised execution of mitochondrial pathway of apoptosis, targeting alternative pathways of cell demise may appear therapeutically beneficial. Herein we report for the first time the effects of an ER-Golgi transport inhibitor, Brefeldin A (BFA), alone and in combination with a small molecule Bcl-2 inhibitor HA14-1 or agonistic anti-Fas mAb, in the recently established human FL cell lines. All cell lines tested were sensitive to BFA-induced cytotoxicity and apoptosis. Moreover BFA-induced cell death was associated with profound ER stress, mitochondrial breach and subsequent caspase cascade activation, including caspase 2 activation. Interestingly, BFA-induced ER stress did not result in appearance of autophagic morphology in FL cells. Of importance, small molecule Bcl-2 antagonist, HA14-1 and agonistic anti-Fas mAb significantly enhanced BFA-mediated cytotoxicity and apoptosis, revealing novel and previously unexplored means to enhance ER stress-mediated cell killing in follicular lymphoma cells.