Ciclopirox activates PERK-dependent endoplasmic reticulum stress to drive cell death in colorectal cancer

Qi, Jianjun; Zhou, Ningning; Li, Liyi; Mo, Shouyong; Zhou, Yuanfei; Deng, Yao; Chen, Ting; Shan, Changliang; Chen, Qin; Lü, Bin

doi:10.1038/s41419-020-02779-1

Cited by 37 publications

(27 citation statements)

References 50 publications

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“…Proteome analyses of HPV16-positive SiHa cervical cancer cells reveal that CPX downregulates factors involved in OXPHOS, in line with its iron-chelating potential [ 35 ], and stimulates factors involved in glycolysis. These findings are also supported by a recent study showing that CPX inhibits mitochondrial respiration and promotes the glycolysis rate in colorectal cancer cells [ 22 ]. Due to OXPHOS inhibition, CPX-treated cells may react particularly sensitive to glucose scarcity.…”

Section: Discussionsupporting

confidence: 81%

“…Among others, CPX inhibits the enzymes ribonucleotide reductase [ 17 ] and deoxyhypusine hydroxylase [ 19 ], downregulates the cell cycle regulators cyclin D1 and E [ 15 ], and inhibits mTORC1 signaling [ 8 , 20 ]. Furthermore, potentially adding to their anti-tumorigenic effects, CPX and other iron chelators can inhibit mitochondrial oxidative phosphorylation (OXPHOS), probably due to decreased activity and expression of the iron-containing enzymes comprising the mitochondrial respiratory complexes [ 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

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Delineating the Switch between Senescence and Apoptosis in Cervical Cancer Cells under Ciclopirox Treatment

Herrmann

Kuhn

Holzer

et al. 2021

Cancers

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The iron-chelating drug ciclopirox (CPX) may possess therapeutic potential for cancer treatment, including cervical cancer. As is observed for other chemotherapeutic drugs, CPX can induce senescence or apoptosis in cervical cancer cells which could differently affect their therapy response. The present study aims to gain insights into the determinants which govern the switch between senescence and apoptosis in cervical cancer cells. We performed proteome analyses, proliferation studies by live-cell imaging and colony formation assays, senescence and apoptosis assays, and combination treatments of CPX with inhibitors of oxidative phosphorylation (OXPHOS) or glycolysis. We found that CPX downregulates OXPHOS factors and facilitates the induction of apoptosis under limited glucose availability, an effect which is shared by classical OXPHOS inhibitors. Under increased glucose availability, however, CPX-induced apoptosis is prevented and senescence is induced, an activity which is not exerted by classical OXPHOS inhibitors, but by other iron chelators. Moreover, we show that the combination of CPX with glycolysis inhibitors blocks cervical cancer proliferation in a synergistic manner. Collectively, our results reveal that the phenotypic response of cervical cancer cells towards CPX is strongly dependent on glucose availability, link the pro-apoptotic and pro-senescent activities of CPX to its bifunctionality as an OXPHOS inhibitor and iron chelator, respectively, and provide a rationale for combining CPX with glycolysis inhibitors.

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Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Delineating the Switch between Senescence and Apoptosis in Cervical Cancer Cells under Ciclopirox Treatment

Herrmann

Kuhn

Holzer

et al. 2021

Cancers

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“…ER stress is considered as one of the mechanisms contributing to ROS-mediated cell death (Qi et al, 2020;Zhao et al, 2020). Therefore, we measured the levels of ER stressrelated proteins in DU145 cells.…”

Section: Iatl and Cisplatin Co-operate To Activate Er Stressmentioning

confidence: 99%

Isoalantolactone Increases the Sensitivity of Prostate Cancer Cells to Cisplatin Treatment by Inducing Oxidative Stress

Huang

et al. 2021

Front. Cell Dev. Biol.

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Prostate cancer is the most common malignancy among men worldwide. Platinum (II)-based chemotherapy has been used to treat a number of malignancies including prostate cancer. However, the potential of cisplatin for treating prostate cancer is restricted owing to its limited efficacy and toxic side effects. Combination therapies have been proposed to increase the efficacy and reduce the toxic side effects. In the present study, we investigated how isoalantolactone (IATL), a sesquiterpene lactone extracted from the medicinal plant Inula helenium L., acts synergistically with cisplatin on human prostate cancer cells. We show that IATL significantly increased cisplatin-induced growth suppression and apoptosis in human prostate cancer cells. Mechanistically, the combined treatment resulted in an excessive accumulation of intracellular reactive oxygen species (ROS), which leads to the activation of endoplasmic reticulum (ER) stress and the JNK signaling pathway in human prostate cancer cells. Pretreatment of cells with the ROS scavenger N-acetylcysteine (NAC) significantly abrogated the combined treatment-induced ROS accumulation and cell apoptosis. In addition, the activation of ER stress and the JNK signaling pathway prompted by IATL and cisplatin was also reversed by NAC pretreatment. In vivo, we found that IATL combined with cisplatin showed the strongest antitumor effects compared with single agents. These results support the notion that IATL and cisplatin combinational treatment may be more effective for treating prostate cancer than cisplatin alone.

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“…CPX can induce cell death in a variety of cancers 3 – 6 ; for example, CPX inhibits tumor growth in xenografts of the human breast cancer cell line, MDA-MB231 3 . Our previous study reported that CPX can activate PERK-dependent endoplasmic reticulum (ER) stress to induce cell death and overcome chemoresistance in colorectal cancer cells 7 . In a phase I clinical trial, CPX showed efficacy and tolerability in the treatment of patients with relapsed or refractory hematologic malignancies 8 .…”

Section: Introductionmentioning

confidence: 99%

Ciclopirox and bortezomib synergistically inhibits glioblastoma multiforme growth via simultaneously enhancing JNK/p38 MAPK and NF-κB signaling

Han

Jin

et al. 2021

Cell Death Dis

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Ciclopirox (CPX) is an antifungal drug that has recently been reported to act as a potential anticancer drug. However, the effects and underlying molecular mechanisms of CPX on glioblastoma multiforme (GBM) remain unknown. Bortezomib (BTZ) is the first proteasome inhibitor-based anticancer drug approved to treat multiple myeloma and mantle cell lymphoma, as BTZ exhibits toxic effects on diverse tumor cells. Herein, we show that CPX displays strong anti-tumorigenic activity on GBM. Mechanistically, CPX inhibits GBM cellular migration and invasion by reducing N-Cadherin, MMP9 and Snail expression. Further analysis revealed that CPX suppresses the expression of several key subunits of mitochondrial enzyme complex, thus leading to the disruption of mitochondrial oxidative phosphorylation (OXPHOS) in GBM cells. In combination with BTZ, CPX promotes apoptosis in GBM cells through the induction of reactive oxygen species (ROS)-mediated c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) signaling. Moreover, CPX and BTZ synergistically activates nuclear factor kappa B (NF-κB) signaling and induces cellular senescence. Our findings suggest that a combination of CPX and BTZ may serve as a novel therapeutic strategy to enhance the anticancer activity of CPX against GBM.

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Ciclopirox activates PERK-dependent endoplasmic reticulum stress to drive cell death in colorectal cancer

Cited by 37 publications

References 50 publications

Delineating the Switch between Senescence and Apoptosis in Cervical Cancer Cells under Ciclopirox Treatment

Delineating the Switch between Senescence and Apoptosis in Cervical Cancer Cells under Ciclopirox Treatment

Isoalantolactone Increases the Sensitivity of Prostate Cancer Cells to Cisplatin Treatment by Inducing Oxidative Stress

Ciclopirox and bortezomib synergistically inhibits glioblastoma multiforme growth via simultaneously enhancing JNK/p38 MAPK and NF-κB signaling

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