Aromatic monophenols from cinnamon bark act as proteasome inhibitors by upregulating ER stress, suppressing FoxM1 expression, and inducing apoptosis in prostate cancer cells

Cinnamon contains bioactive substances with diverse medicinal properties. We investigated the Anticancer potential of abundant Monophenols from cinnamon, namely, cinnamaldehyde, cinnamic acid, and eugenol, by hypothesizing that they possess Proteasome inhibitory activities capable of suppressing Cancer cell proliferation and inducing Apoptosis. This hypothesis was tested by evaluating Proteasome inhibitory activities of the compounds, and assessing downstream molecular and cellular events that are known to be impacted by Proteasome inhibitors. The cinnamon compounds inhibited the catalytic activities of the Proteasome in prostate Cancer cells, but not in normal cells. Treatment with cinnamon compounds or the synthetic Proteasome Inhibitor MG132 upregulated p27 and IkBα proteins, and downregulated FoxM1 and angiogenic markers. These molecular events were associated with the decreased proliferation of prostate Cancer cells. Treatment with cinnamon compounds or MG132 upregulated the expression of genes associated with endoplasmic reticulum (ER) stress/unfolded protein response (BIP, PERK, CHOP, and XBP1(S)). Furthermore, cinnamon compounds or MG132 upregulated the expression of genes required for the assembly of the Caspase-8 activation platform in autophagosomes (LC3B, ATG5, p62, and Beclin1). The Autophagy Inhibitor, 3-methyladenine, blocked the compounds-mediated activation of Caspase-8 and its downstream target Caspase-3. In conclusion, Proteasome inhibition by aromatic Monophenols from cinnamon inhibits proliferation and leads to the death of prostate Cancer cells by autophagy-dependent Apoptosis.