Cucurbitacin I induces cancer cell death through the endoplasmic reticulum stress pathway

Abstract

Endoplasmic reticulum stress (ERS) is usually involved in tumor development and progression, and anticancer agents have recently been recognized to induce ERS. Cucurbitacin‐I showed a potent anticancer action by inducing apoptosis through the inhibition of signal transducer and activator of transcription 3 pathway and triggering autophagic cell death. It is not known whether ERS mediates the cancer cell death induced by cucurbitacin‐I. Here, we investigated the role of ERS in cucurbitacin‐I‐treated SKOV3 ovarian cancer cells and PANC‐1 pancreatic cancer cells. We confirmed that cucurbitacin‐I caused cell death and stirred excessive ERS levels by activating inositol requiring enzyme 1α (IRE1α) and protein kinase R‐like endoplasmic reticulum kinase (PERK), as well as PERK downstream factors, including IRE1α and C/EBP homologous protein, but not activating transcription factor 6 (ATF6α) pathway, which was in parallel with the increased Bax and caspase‐12‐dependent ERS‐associated apoptosis, autophagy and autophagy flux levels and caspase‐independent nonapoptotic cell death. Furthermore, 4‐phenylbutyrate, an ERS inhibitor, suppressed cucurbitacin‐I‐induced apoptosis, autophagy, autophagy flux, and autophagic cell death. Simultaneously, there are positive correlations among ERS and cucurbitacin‐I‐induced reactive oxygen species and Ca 2+. Our results suggested that cucurbitacin‐I‐induced cancer cell death through the excessive ERS and CHOP‐Bax and caspase‐12‐dependent ERS‐associated apoptosis, as well as ERS‐dependent autophagy, autophagy flux, and caspase‐independent nonapoptotic cell death. These novel signaling insights may be useful for developing new, effective anticancer strategies in oncotherapy.

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“…34,35 If ERS increases, apoptotic cascades would be considered an underlying mechanism of MIRI, pathway. [36][37][38] Moreover, ERS in MIRI can be alleviated through the suppression of caspase-12 and CHOP. In this preclinical study, these 3 molecules were highly expressed under H/R or TG induction but dramatically alleviated by DEX and 4-PBA.…”

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

“…Cucurbitacins mediate apoptosis through mitochondrial-related pathway, which is characterized by the loss of the mitochondrial membrane potential, Bcl-2 down-regulation, Bax up-regulation, cytochrome c release, that eventually leads to caspase activation [470,492]. Cucurbitacin I induces cell death through ER stress, by up-regulating ER stress markers such as IRE1α and PERK in human ovarian cancer SKOV3 cells and pancreatic cancer Panc-1 cells [493].…”

Photodynamic therapy regulates fate of cancer stem cells through reactive oxygen species

“…The fate of cells with respect to these two signal cascades depends on the intensity of the photooxidative stress. Severe ER photooxidative stress can stimulate more cascades that are transducing death-promoting signals (such as apoptosis), such as that stimulated by CCAAT/enhancer binding protein homologous protein, which is a key pro-apoptotic transcription factor in ERS[ 152 , 153 ]. A small or low level of ER photooxidative stress can stimulate more promoting survival signaling cascades (such as autophagy, p38 mitogen-activated protein kinase(MAPK) signaling, antioxidant signaling, and amino-terminal kinase JNK signaling)[ 154 , 155 ].…”