A Triterpene Lactone from Callistemon citrinus Inhibits the PANC‐1 Human Pancreatic Cancer Cells Viability through Suppression of Unfolded Protein Response

Abstract

Human pancreatic tumor cells such as PANC-1 are known for their ability to tolerate nutrient starvation and thrive under the hypovascular tumor microenvironment, a phenomenon termed as 'austerity'. A search of agents that preferentially inhibit the cancer cell viability under the starvation condition without toxicity in the nutrientrich condition is a promising approach in anticancer drug discovery. In this study, a triterpene lactone, 3βhydroxy-13,28-epoxyurs-11-en-28-one (ursenolide), isolated from a Callistemon citrinus extract has shown strong preferential cytotoxicity against PANC-1 cells under nutrient starvation with PC 50 value of 0.4 μM. Ursenolideinduced rounding of PANC-1 cell morphology followed by rupture of the cell membrane leading to cell death. In a real-time cell migration study, ursenolide was found to inhibit PANC-1 cell migration significantly. Mechanistically, it inhibited GRP78 and GRP94 under the starvation condition suggesting inhibition of unfolded protein response (UPR), an adaptive process of cell survival during starvation. It also inhibited the phosphorylation of the key survival protein Akt and mTOR. Overall results suggested that ursenolide is a potential anticancer agent against pancreatic cancer.

GDP Induces PANC‐1 Human Pancreatic Cancer Cell Death Preferentially under Nutrient Starvation by Inhibiting PI3K/Akt/mTOR/Autophagy Signaling Pathway

“…At the highest concentration of GDP (100 μM), colony formation was reduced by over 80 % compared to the control cells. These results prove the inhibitory effect of GDP on pancreatic cancer colony formation, similar to many previously discovered antiausterity agents, such as ancistrolikokine E3, callistrilone L, and ursenolide [11,20,23] …”

“…Quantitive real‐time cancer cell migration inhibition studies have rarely been reported. Callistrilone L and ursenolide, two potent anti‐austerity agents recently reported by our group, exerted remarkable cell migration inhibitory activities against PANC‐1 cells in real‐time [11,20] . In continuation, we herein also provide quantitative real‐time live‐evidence of the PANC‐1 cancer cell migration inhibition by GDP [21] .…”

“…Therefore, inhibiting the autophagy pathway may promote cancer cell death [30] . Several anti‐austerity agents, such as ancistrolikokine E3 and ursenolide, were found to inhibit both the Akt/mTOR and autophagy activation pathways [20,23] . In the present study, GDP was also found to inhibit the expression of autophagosome‐bound marker microtubule‐associated protein light chain 3 (LC3‐II) in a concentration‐dependent manner within 6 h ( Figure 6).…”

“…In the present study, GDP was also found to inhibit the expression of autophagosome‐bound marker microtubule‐associated protein light chain 3 (LC3‐II) in a concentration‐dependent manner within 6 h ( Figure 6). These results suggested GDP could inhibit the survival of PANC‐1 cells under nutrient‐deprived conditions through the inhibition of the PI3K/Akt/mTOR/autophagy signaling pathway, and GDP primarily inhibits the phosphorylation of Akt, similar to ancistrolikokine E3, and ursenolide [20,23] …”

Unfolded protein response activated by endoplasmic reticulum stress in pancreatic cancer: potential therapeutical target

“…ER plays a key role in protein modification, folding and degradation. However, pancreatic tumor microenvironment disrupts ER homeostasis and affects protein folding, and induces ER stress [32].…”