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

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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

Ciclopirox (CPX) modulates multiple cellular pathways involved in the growth of a variety of tumor cell types. However, the effects of CPX on colorectal cancer (CRC) and the underlying mechanisms for its antitumor activity remain unclear. Herein, we report that CPX exhibited strong antitumorigenic properties in CRC by inducing cell cycle arrest, repressing cell migration, and invasion by affecting N-cadherin, Snail, E-cadherin, MMP-2, and MMP-9 expression, and disruption of cellular bioenergetics contributed to CPX-associated inhibition of cell growth, migration, and invasion. Interestingly, CPX-induced reactive oxygen species (ROS) production and impaired mitochondrial respiration, whereas the capacity of glycolysis was increased. CPX (20 mg/kg, intraperitoneally) substantially inhibited CRC xenograft growth in vivo. Mechanistic studies revealed that the antitumor activity of CPX relies on apoptosis induced by ROS-mediated endoplasmic reticulum (ER) stress in both 5-FU-sensitive and -resistant CRC cells. Our data reveal a novel mechanism for CPX through the disruption of cellular bioenergetics and activating protein kinase RNA-like endoplasmic reticulum kinase (PERK)-dependent ER stress to drive cell death and overcome drug resistance in CRC, indicating that CPX could potentially be a novel chemotherapeutic for the treatment of CRC.

Deferoxamine suppresses esophageal squamous cell carcinoma cell growth via ERK1/2 mediated mitochondrial dysfunction.

Deferoxamine (DFO) was found to modulate multiple cellular pathways involved in the growth of breast cancer, hepatocellular carcinoma, lung cancer and bladder cancer. However, the effect of DFO on esophageal squamous cell carcinoma (ESCC) remains unclear. Here, we report that DFO-treated ESCC cells show strong anti-tumorigenic properties, such as inhibition of cell proliferation, induction of cell cycle arrest, and promotion of apoptosis. Mechanistically, DFO significantly activated ERK1/2 signaling, which is reactive oxygen species (ROS)-dependent. ERK1/2 activation suppressed mitochondrial respiration and aerobic glycolysis in ESCC cells, resulting in reduced production of ATP and key precursor metabolites. Cell proliferation was functionally rescued by the ROS scavenger N-acetyl-l-cysteine (NAC) and the ERK1/2 inhibitor SCH7 72984. Additionally, our data showed that activated ERK1/2 was partially translocated to the mitochondria, which indicated that DFO-activated ERK1/2 may suppress tumor formation through inhibition of mitochondrial respiration. Moreover, the decreased c-Myc expression caused by DFO resulted in the inhibition of cell migration. Taken together, our study demonstrate that DFO activates ERK1/2 and downregulates c-Myc to perturb mitochondrial homeostasis and promote apoptosis, resulting in the novel anti-neoplastic activity of DFO in ESCC.

Oxidative stress regulates cellular bioenergetics in esophageal squamous cell carcinoma cell.

The aim of the present study was to explore the effects of oxidative stress induced by CoCl2 and H2O2 on the regulation of bioenergetics of esophageal squamous cell carcinoma (ESCC) cell line TE-1 and analyze its underlying mechanism. Western blot results showed that CoCl2 and H2O2 treatment of TE-1 cells led to significant reduction in mitochondrial respiratory chain complex subunits expression and increasing intracellular reactive oxygen species (ROS) production. We further found that TE-1 cells treated with CoCl2, a hypoxia-mimicking reagent, dramatically reduced the oxygen consumption rate (OCR) and increased the extracellular acidification rate (ECAR). However, H2O2 treatment decreased both the mitochondrial respiration and aerobic glycolysis significantly. Moreover, we found that H2O2 induces apoptosis in TE-1 cells through the activation of PARP, Caspase 3, and Caspase 9. Therefore, our findings indicate that CoCl2 and H2O2 could cause mitochondrial dysfunction by up-regulation of ROS and regulating the cellular bioenergy metabolism, thus affecting the survival of tumor cells.

Paclitaxel induces apoptosis of esophageal squamous cell carcinoma cells by downregulating STAT3 phosphorylation at Ser727.

Paclitaxel induces apoptosis in a variety of cancer cells. However, the mechanism of paclitaxel inducing apoptosis in human esophageal squamous cell carcinoma (ESCC) remains to be defined. In this study, we found that paclitaxel-induced apoptosis by increasing the relevant apoptosis protein expression and the release of cytochrome c via downregulation of signal transducer and activator of transcription 3 (STAT3) and phospho-STAT3 (Ser727). In addition, paclitaxel treatment of ESCC cells EC-1 and Eca-109 led to marked mitochondrial membrane potential depolarization and significantly increasing of reactive oxygen species. Moreover, paclitaxel treatment resulted in the inhibition of mitochondrial respiration. In conclusion, our findings reveal that paclitaxel induced apoptosis in both EC-1 and Eca-109 cells through the reduction of STAT3 and phospho­STAT3 (Ser727) level, and suggest that paclitaxel may be of therapeutic potential in the treatment of ESCC through the induction of mitochondrial apoptosis in ESCC cells.