Abstract
The antiapoptotic and antiautophagic abilities of cancer cells constitute a major challenge for anticancer drug treatment. Strategies for triggering nonapoptotic or nonautophagic cell death may improve therapeutic efficacy against cancer. Curcumin has been reported to exhibit cancer chemopreventive properties. Herein, we report that curcumin induced apoptosis in LNCaP, DU145, and PC-3 cells but triggered extensive cytoplasmic vacuolation in PC-3M cells. Electron microscopic images showed that the vacuoles lacked intracellular organelles and were derived from the endoplasmic reticulum (ER). Moreover, curcumin-induced vacuolation was not reversed by an apoptosis- or autophagy-related inhibitor, suggesting that vacuolation-mediated cell death differs from classical apoptotic and autophagic cell death. Mechanistic investigations revealed that curcumin treatment upregulated the ER stress markers CHOP and Bip/GRP78 and the autophagic marker LC3-II. In addition, curcumin induced ER stress by triggering ROS generation, which was supported by the finding that treating cells with the antioxidant NAC alleviated curcumin-mediated ER stress and vacuolation-mediated death. An in vivo PC-3M orthotopic prostate cancer model revealed that curcumin reduced tumor growth by inducing ROS production followed by vacuolation-mediated cell death. Overall, our results indicated that curcumin acts as an inducer of ROS production, which leads to nonapoptotic and nonautophagic cell death via increased ER stress.
Highlights
Several forms of nonapoptotic and nonautophagic cell death, such as oncosis[7], necroptosis[8], entosis[9], anoikis[10], and programmed necrosis[11], have been described according to specific cellular and molecular criteria
A previous report indicated that increased expression of the autophagic marker LC3-II and the endoplasmic reticulum (ER) stress markers Bip/GRP78 and CHOP or the accumulation of ubiquitinated proteins is observed in cancer cells undergoing cytoplasmic vacuolation-mediated death[15]
Recent studies have indicated that ER stress may contribute to caspase-independent cell death, which is characterized by extensive cytoplasmic vacuolation in cancer cells without the involvement of apoptosis or autophagy[12,13]
Summary
Several forms of nonapoptotic and nonautophagic cell death, such as oncosis[7], necroptosis[8], entosis[9], anoikis[10], and programmed necrosis[11], have been described according to specific cellular and molecular criteria. Recent studies have indicated that ER stress may contribute to caspase-independent cell death, which is characterized by extensive cytoplasmic vacuolation in cancer cells without the involvement of apoptosis or autophagy[12,13]. Our results showed that curcumin was able to inhibit the growth of metastatic PC-3M prostate cancer cells in a highly potent manner by inducing the ROS-mediated activation of ER stress and, subsequently, nonapoptotic and nonautophagic cytoplasmic vacuolation-mediated cell death. An increase in ROS generation and ER stress was observed in curcumin-induced vacuolation-mediated cell death in a PC-3M orthotopic graft model. These findings suggest, for the first time, that curcumin may represent a novel agent for metastatic prostate cancer treatment
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