Abstract
Geranylated 4-phenylcoumarins DMDP-1 and DMDP-2 isolated from Mesua elegans were elucidated for their role in inducing caspase-independent programmed cell death (CI-PCD) in prostate cancer cell lines, PC-3 and DU 145, respectively. Cell homeostasis disruption was demonstrated upon treatment, as shown by the increase in calcium ion through colourimetric assay and endoplasmic reticulum (ER) stress markers GRP 78 and p-eIF2α through western blot. Subsequently, cytoplasmic death protease calpain-2 also showed increased activity during DMDP-1 & -2 treatments, while lysosomic death protease cathepsin B activity was significantly increased in PC-3 treated with DMDP-1. Flow cytometry showed a reduction in mitochondrial membrane potential in both cell lines, while western blotting showed translocation of mitochondrial death protease AIF into the cytoplasm in its truncated form. Furthermore, DMDP-1 & -2 treatments caused significant increase in superoxide level and oxidative DNA damage. Concurrent inhibition of calpain-2 and cathepsin B during the treatment showed an attenuation of cell death in both cell lines. Hence, DMDP-1 & -2 induce CI-PCD in prostate cancer cell lines through calpain-2 and cathepsin B.
Highlights
Geranylated 4-phenylcoumarins DMDP-1 and DMDP-2 isolated from Mesua elegans were elucidated for their role in inducing caspase-independent programmed cell death (CI-Programmed cell death (PCD)) in prostate cancer cell lines, PC-3 and DU 145, respectively
Programmed cell death (PCD), or apoptosis, is a natural process that maintains homeostasis in living organisms. While this is the most conventional cell death pathway involving the activation of caspases (CD-PCD), there is an alternative mechanism known as caspase-independent PCD (CI-PCD)
Increase in intracellular Ca2+ level is important in the activation of the calcium-dependent calpain-212
Summary
Geranylated 4-phenylcoumarins DMDP-1 and DMDP-2 isolated from Mesua elegans were elucidated for their role in inducing caspase-independent programmed cell death (CI-PCD) in prostate cancer cell lines, PC-3 and DU 145, respectively. DMDP-1 & -2 induce CI-PCD in prostate cancer cell lines through calpain-2 and cathepsin B. Prostate cancer is one of the most frequently reported cancers in men worldwide with 1.8 million cases in 2018 It is commonly diagnosed in elderly men, with a high incidence rate in France, Ireland and the United States, predominantly due to the lifestyle in these developed countries[1,2]. Many natural compounds have been reported to induce CI-PCD in different cell lines, such as berberine in colon cancer and thymoquinone in glioblastoma through activation of cathepsin B5,6. Results were presented as mean normalized intensity ± S.D. of three independent experiments and (*) is used to denote p < 0.05
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