Zerumbone, a ginger sesquiterpene, induces apoptosis and autophagy in human hormone-refractory prostate cancers through tubulin binding and crosstalk between endoplasmic reticulum stress and mitochondrial insult

Abstract

Zerumbone, a natural monocyclic sesquiterpene, is the main component of the tropical plant Zingiber zerumbet Smith. Zerumbone induced antiproliferative and apoptotic effects against PC-3 and DU-145, two human hormone-refractory prostate cancer (HRPC) cell lines. Zerumbone inhibited microtubule assembly and induced an increase of MPM-2 expression (specific recognition of mitotic proteins). It also caused an increase of phosphorylation of Bcl-2 and Bcl-xL, two key events in tubulin-binding effect, indicating tubulin-binding capability and mitotic arrest to zerumbone action. Furthermore, zerumbone induced several cellular effects distinct from tubulin-binding properties. First, zerumbone significantly increased, while paclitaxel (as a tubulin-binding control) decreased, Mcl-1 protein expression. Second, paclitaxel but not zerumbone induced Cdk1 activity. Third, zerumbone other than paclitaxel induced Cdc25C downregulation. The data suggest that, in addition to targeting tubulin/microtubule, zerumbone may act on other targets for signaling transduction. Zerumbone induced mitochondrial damage and endoplasmic reticulum (ER) stress as evidenced by the loss of mitochondrial membrane potential and upregulation of GRP-78 and CHOP/GADD153 expression. Zerumbone induced an increase of intracellular Ca(2+) levels, a crosstalk marker between ER stress and mitochondrial insult, associated with the formation of active calpain I fragment. It induced apoptosis through a caspase-dependent way and caused autophagy as evidenced by dramatic LC3-II formation. In summary, the data suggest that zerumbone is a multiple targeting compound that inhibits tubulin assembly and induces a crosstalk between ER stress and mitochondrial insult, leading to apoptosis and autophagy in HRPCs.

Comparison of the Complications of Platinum-Based Adjuvant Chemotherapy With and Without Ginger in a Pilot Study on Ovarian Cancer Patients

“…In a study by Chan et al, ginger extract could destroy prostate cancer cells at the cellular level. Such an anticancer effect was achieved through binding to tubulin and establishing a connection between endoplasmic reticulum stress and mitochondrial damage (45). A similar result was reported by Saha et al (46).…”

Emerging Anti-Mitotic Activities and Other Bioactivities of Sesquiterpene Compounds upon Human Cells

“…It arrests treated cells in the G 2 /M-phase of the cell cycle in a time (24, 48, and 72 h) and concentration (26, 42, and 57 µM) dependent manner, followed by apoptosis [ 125 ]. Chan et al found that 30 µM zerumbone had anti-proliferative activity to PC-3 and DU-145 prostate cancer cell lines inducing a G 2 /M-phase arrest at 8 h, and increased the levels of PH3, cyclin B, and MPM2 expression, a mitotic marker [ 126 ]. It was shown that zerumbone caused a mitotic arrest by targeting tubulin/microtubules and disrupting microtubule dynamics, which led to the formation of aberrant monopolar and multipolar spindles [ 126 ].…”

“…Chan et al found that 30 µM zerumbone had anti-proliferative activity to PC-3 and DU-145 prostate cancer cell lines inducing a G 2 /M-phase arrest at 8 h, and increased the levels of PH3, cyclin B, and MPM2 expression, a mitotic marker [ 126 ]. It was shown that zerumbone caused a mitotic arrest by targeting tubulin/microtubules and disrupting microtubule dynamics, which led to the formation of aberrant monopolar and multipolar spindles [ 126 ]. The authors described other effects upon cells treated with zerumbone, which included endoplasmic reticulum stress and mitochondria-mediated apoptosis.…”

“…The authors described other effects upon cells treated with zerumbone, which included endoplasmic reticulum stress and mitochondria-mediated apoptosis. In addition to caspase-dependent apoptosis, zerumbone also induced autophagic cell death mediated by a decrease of light chain 3 (LC3), a marker for autophagy [ 126 , 127 ]. Xian et al reported that a 24 h treatment of NB4 leukemia cells with 10 µM zerumbone arrested them in the G 2 phase of the cell cycle, as characterized by phosphorylation of Cdk1 on Tyr15.…”

The Natural Occurring Compounds Targeting Endoplasmic Reticulum Stress

“…Zerumbone is a natural monocyclic sesquiterpene from Zingiber zerumbet Smith. It has been investigated that zerumbone may induce apoptosis and autophagy in PC-3 and DU-145 cells through ER stress induction and mitochondrial dysfunction [ 108 ].…”