Paclitaxel Induces the Apoptosis of Prostate Cancer Cells via ROS-Mediated HIF-1α Expression

Abstract

Prostate cancer (PCa) is the most common malignancy to endanger the health of male genitourinary system. Clinically, paclitaxel (PTX) (C47H51NO14), a diterpene alkaloid, is commonly used as an effective natural antineoplastic drug during the treatment of PCa. However, the mechanism and pathway involved in the function of PTX are poorly understood. In the current study, we employed the CCK-8 assay, revealing that PTX can inhibit the survival and induce the apoptosis of PC3M cells (a human prostate cancer cell line) in a concentration-dependent manner. Reactive oxygen species (ROS), as a metabolic intermediate produced by the mitochondrial respiratory chain, are highly accumulated under the PTX treatment, which results in a sharp decrease of the mitochondrial membrane potential in PC3M cells. Additionally, the migration and invasion of PC3M cells are weakened due to PTX treatment. Further analysis reveals that N-acetylcysteine (NAC), which functions as an antioxidant, not only rescues the decreased mitochondrial membrane potential induced by the abnormal ROS level, but also restores the migration and invasion of PC3M cells. In a subsequent exploration of the detailed mechanism, we found that hypoxia-inducible factor (HIF)-1α works as a downstream gene that can respond to the increased ROS in PC3M cells. Under PTX treatment, the expression levels of HIF-1α mRNA and protein are significantly increased, which stimulate the activation of JNK/caspase-3 signaling and promote the apoptosis of PC3M cells. In summary, we demonstrate that PTX regulates the expression of HIF-1α through increased ROS accumulation, thereby promoting the activation of JNK/caspase-3 pathway to induce the apoptosis of PCa cells. This study provides new insights into the mechanism of antineoplastic action of taxanes and unveils the clinical benefit of the ROS-HIF-1α signaling pathway, which may offer a potential therapeutic target to prevent the development of PCa.

Auranofin sensitizes breast cancer cells to paclitaxel chemotherapy by disturbing the cellular redox system

“…Disturbance of microtubule polymerization by paclitaxel renders Rac1 stabilization in the active NOX complex, leading to increased ROS generation 7 . Further, it has also been reported that paclitaxel induces the apoptosis of prostate cancer cells via ROS‐mediated hypoxia‐inducible factor‐1α expression 52 . As the auranofin treatment inhibits the cellular redox system, it will synergistically improve paclitaxel‐induced ROS generation in the breast cancer cells.…”

“…7 Further, it has also been reported that paclitaxel induces the apoptosis of prostate cancer cells via ROS-mediated hypoxia-inducible factor-1α expression. 52 As the auranofin treatment inhibits the cellular redox system, it will synergistically improve paclitaxel-induced ROS generation in the breast cancer cells. DRG cells.…”

Deguelin Restores Paclitaxel Sensitivity in Paclitaxel-Resistant Ovarian Cancer Cells via Inhibition of the EGFR Signaling Pathway

“…Next, we attempted to examine the mechanism by which deguelin inhibits paclitaxel resistance in SKOV3-TR cells. Several reports indicated that the mechanism of cell death caused by paclitaxel treatment may be due to excessive 18,78 To determine whether ROS mediates the cell cytotoxicity in SKOV3-TR cells cotreated with deguelin and paclitaxel, we additionally treated NAC and then examined cell viability by WST-1 analysis. Figure 5A showed that NAC did not inhibit cell cytotoxicity induced by cotreatment with deguelin and paclitaxel in SKOV3-TR cells.…”

Oxidative Stress Inducers in Cancer Therapy: Preclinical and Clinical Evidence

“…This prevents the disassembly of microtubules and consequently induces mitotic arrest, which in turn induces cell death [ 157 ]. ROS induction has been suggested as a secondary/alternative mechanism of action of paclitaxel and has been reported in osteosarcoma [ 158 ], prostate cancer [ 159 ], and non-small-cell lung cancer [ 160 ] cells. However, of these studies, only one reported that the use of the ROS scavenger N-acetylcysteine abrogated paclitaxel-mediated effects [ 159 ].…”

“…ROS induction has been suggested as a secondary/alternative mechanism of action of paclitaxel and has been reported in osteosarcoma [ 158 ], prostate cancer [ 159 ], and non-small-cell lung cancer [ 160 ] cells. However, of these studies, only one reported that the use of the ROS scavenger N-acetylcysteine abrogated paclitaxel-mediated effects [ 159 ]. Moreover, it has only recently been clarified that mitochondrial accumulation, a consequence of paclitaxel-induced mitotic arrest, causes mitochondrial oxidative stress [ 161 ].…”