Camptothecin Induces Apoptosis in Cancer Cells via MicroRNA-125b-Mediated Mitochondrial Pathways

Abstract

Camptothecin (CPT) is an effective chemotherapeutic agent for treatment of patients with cancer. The mechanisms underlying CPT-mediated responses in cancer cells are not fully understood. MicroRNA (miRNA) play important roles in tumorigenesis and drug sensitivity. However, the interaction between camptothecin and miRNA has not been previously explored. In this study, we verified that miR-125b was down-regulated in CPTinduced apoptosis in cancer cells and that ectopic expression of miR-125b partially restored cell viability and inhibited cell apoptosis that was induced by CPT. In addition, we demonstrated that CPT induced apoptosis in cancer cells by miR125b-mediated mitochondrial pathways via targeting to the 3Ј-untranslated (UTR) regions of Bak1, Mcl1, and p53. A significant increase in Bak1, Mcl1, and p53 protein levels was detected in response to the treatments of CPT. It is noteworthy that the expression levels of Bak1, Mcl1, and p53 increased in a time-dependent manner and negatively correlated with miR125b expression. It is noteworthy that we revealed that miR125b directly targeted the 3ЈUTR regions of multiple genes in a CPT-induced mitochondrial pathway. In addition, most targets of miR-125b were proapoptotic genes, whereas some of the targets were antiapoptotic genes. We hypothesized that miR125b may mediate the activity of chemotherapeutic agents to induce apoptosis by regulating multiple targets. This is the first report to show that camptothecin induces cancer cell apoptosis via miRNA-mediated mitochondrial pathways. The results suggest that suppression of miR-125b may be a novel approach for the treatment of cancer.

The Natural Inhibitor of DNA Topoisomerase I, Camptothecin, Modulates HIF-1α Activity by Changing miR Expression Patterns in Human Cancer Cells

“…Interestingly, modifications of levels of several miRNAs after camptothecin treatments in normoxic cancer cells have been related to resistance or sensitivity to Top1 inhibitors (41)(42)(43)(44). Overall, these studies confirm that different concentrations of Top1 inhibitors finely modulate the balance of cellular miRNAs levels.…”

Pseudomonas aeruginosa ExoT Induces Mitochondrial Apoptosis in Target Host Cells in a Manner That Depends on Its GTPase-activating Protein (GAP) Domain Activity

“…MitoCapture is a cationic dye that accumulates and aggregates in intact mitochondria, resulting in punctate staining, but remains in the cytoplasm in its monomeric form upon disruption of the mitochondrial membrane potential, exhibiting diffuse staining. As a positive control, uninfected HeLa cells were treated with camptothecin, a known inducer of the mitochondrial intrinsic pathway (28). As shown in Fig.…”

miR-125b controls monocyte adaptation to inflammation through mitochondrial metabolism and dynamics

“…[12][13][14][15][16][17] Depending on the cellular context, miR-125b shows different patterns of expression and effects, acting as a tumor suppressor gene or oncogene through the regulation of multiple genes involved in the mitochondrial pathways of apoptosis. [18][19][20][21] In hematopoietic stem cells, miR-125b is highly expressed, enhancing self-renewal and survival while providing resistance to apoptosis and blocking differentiation, and is upregulated in lymphoblastic and myeloblastic leukemia. 22 Importantly, miR-125b plays a critical role in myeloid biology, 23 with its expression being low in common myeloid progenitors, 22 induced upon inflammatory stimuli in macrophages, 24,25 and deregulated in myeloid malignancies.…”