Thymoquinone Suppresses the Proliferation, Migration and Invasiveness through Regulating ROS, Autophagic Flux and miR-877-5p in Human Bladder Carcinoma Cells

Abstract

Bladder carcinoma is among the top 10 most frequently diagnosed cancer types in the world. As a phytochemical active metabolic, thymoquinone (TQ) is extracted from seeds of Nigella sativa, possessing various biological properties in a wide range of diseases. Moreover, the outstanding anti-cancer effect of TQ is attracting increasing attentions. In certain circumstances, moderate autophagy is regarded to facilitate the adaptation of malignant cells to different stressors. Conversely, closely linked with the mitochondrial membrane potential (MMP) loss, the upregulation of intracellular reactive oxygen species (ROS) is reported to activate the cell apoptosis in many cancer types. Furthermore, the vital effects of microRNAs in the pathological processes of cancer cells have also been confirmed by previous studies. The present research confirms that TQ restrains the viability, proliferation, migration and invasion through activating caspase-dependent apoptosis in bladder carcinoma cells, which is mediated by TQ induced ROS increase in bladder carcinoma cells. Furthermore, TQ is proved to block the fusion of autophagosomes and lysosomes, causing the accumulation of autophagosomes and subsequent cell apoptosis. In addition, TQ is also found to initiate the miR-877-5p/PD-L1 axis, which suppresses the epithelial mesenchymal transition (EMT) and invasion of bladder carcinoma cells. Taken together, TQ induces the apoptosis through upregulating ROS level and impairing autophagic flux, and inhibiting the EMT and cell invasion via activating the miR-877-5p/PD-L1 axis in bladder carcinoma cells.

RETRACTED: Trehalose improves palmitic acid‐induced apoptosis of osteoblasts by regulating SIRT3‐medicated autophagy via the AMPK/mTOR/ULK1 pathway

“…Moderate autophagy has the positive effect to resist stress damage and inhibit cellular apoptosis. 15 Trehalose protected many pathological conditions-induced apoptosis by promoting autophagy. 16,17 All this evident indicated that Trehalose might prevent the lipotoxicity-induced apoptosis of osteoblasts by enhancing autophagy.…”

Plants as a Source of Anticancer Agents: From Bench to Bedside

“…MiRNAs are small noncoding RNAs that modulate gene expression and cellular signaling pathways through variation in the features of mRNA, thus moderating TQ’s anticancer effect through P53, PCNA, cyclin D1, Bcl-2, NF-κB, TWIST (Twist1,2), ZEB, eEF-2 K, PI3K/Akt, and Src/Fak signaling pathways [ 247 ]. Along with TQ’s impairment of autophagic flux and inhibition of the EMT and cell invasion via activation of the miR-877-5p/PD-L1 (programmed death ligand 1) axis in bladder carcinoma cells and the expression of Beclin-1 and LC3 in triple-negative breast cancer (TNBC) cells, it suppresses the pathways related to cell migration/invasion and angiogenesis, including Integrin-β1, VEGF, MMP-2, and MMP-9 [ 248 , 249 ]. Thymoquinone upregulates miR-125a-5p, attenuates STAT3 activation, and potentiates doxorubicin antitumor activity in murine solid Ehrlich carcinoma [ 250 ].…”

Anticancer and Anti-Metastatic Role of Thymoquinone: Regulation of Oncogenic Signaling Cascades by Thymoquinone

“…hsa-miR-877-5p levels were found to be enhanced in tumor xenografts in mice inoculated with T24 cells. Moreover, thymoquinone profoundly suppressed the number of pulmonary metastatic nodules in mice injected with bladder cancer cells [ 99 ].…”