Abstract
Fluvastatin (FLV) is a statin family member that may play a role in modulating a variety of medical disorders such as atherosclerosis and breast cancer. The present study addresses the ability of FLV to modulate the cellular immune response and provides a new nanosized FLV formula (self-nanoemulsifying delivery system, SNED) potentially more effective for suppression of breast cancer development. We monitored autophagic machinery through the expression of microtubule-associated protein 1A/1B-light chain 3 (LC3I/II). Lysosomal activity upon treatment was evaluated by mRNA and protein expression of lysosomal-associated membrane protein 1 (LAMP-1). Mitogen-activated protein kinase (MAPK) signaling and its association with proinflammatory cytokine secretion were assessed in treated cells. Autophagosome formation was significantly increased in cells that were pretreated with FLV-SNED in comparison to FLV-treated cells. Activation of autophagy was accompanied with arrest of LAMP-1 expression, which correlates with lysosomal activity. Simultaneously, both FLV and FLV-SNED activated MAPK signaling and modified interleukin-6 and tumor necrosis factor-α levels in treated cells. These findings indicate that FLV reduces cell viability via depletion of lysosomal activities along with accumulation of autophagosomes leading to disturbance of autophagosome-lysosomal fusion in treated cells. Furthermore, our data reveal the effectiveness of both FLV agents in the modulation of proinflammatory cytokine secretion from treated cells via regulation of MAPK signaling cascades and indicate that FLV-SNED is more efficient than FLV. This study provides new insights into how FLV regulates breast cancer cell viability via modulation of AMPK-mTOR and ERK-mTOR signaling, and through autophagosome formation accompanied by lysosomal degradation.