Autophagic and apoptotic cell death induced by the quinoline derivative 2‐(6‐methoxynaphthalen‐2‐yl)quinolin‐4‐amine in pancreatic cancer cells is via ER stress and inhibition of Akt/mTOR signaling pathway

Abstract

AbstractPancreatic cancer (PC) is among the most lethal cancers and is resistant to existing therapies, which highlights the need for new and alternative therapeutic treatments. Autophagy is emerging as one of the alternative cell death mechanisms and is well known to cross‐talk with apoptosis. Autophagy can act as a viable option to treat highly resistant PC. The current study investigates and provides insight into the autophagic and apoptotic cell death induced by quinoline derivative 2‐(6‐methoxynaphthalen‐2‐yl)quinolin‐4‐amine (6MN‐4‐AQ) in PC cell lines PANC‐1 and MIA PaCa‐2. Treatment with 6MN‐4‐AQ reduced cell viability in concentration dependent manner (2–16 μM) and inhibited the clonogenic potential of PC cells at a concentration of 4 μM for 24 h. Further, we found that 6MN‐4‐AQ induced both apoptosis and autophagic cell death simultaneously. We identified that 6MN‐4‐AQ induced autophagic cell death by forming cytoplasmic vacuoles, the elevation of autophagy flux, increase in LC3‐II, Beclin‐1 protein expression, and degradation of p62. Moreover, 6MN‐4‐AQ induced apoptosis via Caspase‐3 activation and cleavage of PARP in PC cells. Upon investigating the underlying mechanism associated with 6MN‐4‐AQ induced cell death, it was observed that 6MN‐4‐AQ treatment is able to suppress the Akt/mTOR pathway and induced ER stress leading to the induction of autophagy. Also, 6MN‐4‐AQ treatment suppressed epithelial to mesenchymal transition by reducing the protein expression of SLUG, snail, and vimentin. Subsequently, 6MN‐4‐AQ inhibited cell migration and invasion by down regulating MMP‐7 and MMP‐9 protein expression, suggesting that 6MN‐4‐AQ may serve as a plausible therapeutic agent for PC.