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

Abstract

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.

Therapeutic Effects of Essential Oils and Their Bioactive Compounds on Prostate Cancer Treatment

“…Moreover, apoptosis occurred through the inhibition of 26S proteasome activity, the induction of a dose-dependent increase in caspase-3 activity, a decrease in Akt protein levels and a decrease in anti-apoptotic (Survivin and XIAP) and angiogenic (VEGF and VEGF receptor) gene markers' expression in both cancer cells lines [110]. An HPLC analysis of this aqueous cinnamon extract revealed the presence of high amounts of cinnamaldehyde [86].…”

“…In addition, cinnamon compounds downregulated the expression of angiogenic factors (VEGF and VEGFR), acting as antiangiogenic agents. The treatment of tumor cells with cinnamon compounds also led to a dose-dependent decrease in cell viability with IC 50 values of 14.3 µM for cinnamaldehyde, 73.2 µM for eugenol and 6.2 µM for cinnamic acid [86]. Eugenol also inhibits the growth of DU145 cells [90].…”

“…Inhibition of cell growth, migration, and invasion; decreased TRPM7-like current and reduced MMP-2 protein expression and F-actin dynamics; alterations of PI3K/Akt and MEK/MAPK signaling pathways[84,85] Cinnamaldehyde Cinnamon PC3 and LNCaP Inhibition of cell growth and proteasome activity; upregulated Hsp70 and downregulated VEGF and VEGFR expression[86] Prostate CAF Inhibition of cell growth, induction of apoptosis induction, cell cycle arrest, increased ROS generation and caspase activation and decreased GSH levels[87] Prostate CAF Relieves the immunosuppressive effects in a TLR4-dependent manner[88] …”

Cinnamaldehyde: Pharmacokinetics, anticancer properties and therapeutic potential (Review)

“…The proteasome is an anticancer target, and proteasome inhibition can promote apoptosis and inhibit tumor growth ( 78 , 79 ). Gopalakrishnan and Ismail ( 80 ) found that cinnamon compounds can inhibit the activity of the proteasome, leading to the accumulation of p27 protein, thereby inhibiting the proliferation of prostate cancer cells. Meanwhile, cinnamon compounds also lead to downregulation of vascular endothelial growth factor A (VEGFA) and VEGF receptor, thereby inhibiting the angiogenic capability of tumor cells.…”

Oncogenic role of FOXM1 in human prostate cancer (Review)

“…By contrast, FOXM1 knockdown induces prostate cancer cell apoptosis (26,48). In addition, FOXM1 inhibition by miRNAs (e.g., miR-193b) or chemical compounds [e.g., forkhead domain inhibitory compound-6 (FDI-6), niclosamide, siomycin A, SR9009, morusin, cinnamaldehyde, cinnamic acid and eugenol] was reported to induce apoptosis (23,26,27,33,50,52,53).…”