Metastatic effects of environmental carcinogens mediated by MAPK and UPR pathways with an in vivo Drosophila Model

Metastasis includes tumor invasion and migration and underlies over 90% of cancer mortality. The metastatic effects of environmental carcinogens raised serious health concerns. However, the underlying mechanisms remained poorly studied. In the present study, an in vivo RasV12/lgl-/- model of the fruitfly, Drosophila melanogaster, with an 8-day exposure was employed to explore the metastatic effects of 3,3',4,4',5-pentachlorobiphenyl (PCB126), perfluorooctanoic acid (PFOA) and cadmium chloride (CdCl2). At 1.0 mg/L, PCB126, PFOA, and CdCl2 significantly increased tumor invasion rates by 1.32-, 1.33-, and 1.29-fold of the control, respectively. They also decreased the larval body weight and locomotion behavior. Moreover, they commonly disturbed the expression levels of target genes in MAPK and UPR pathways, and their metastatic effects were significantly abolished by the addition of p38 inhibitor (SB203580), JNK inhibitor (SP600125) and IRE1 inhibitor (KIRA6). Notably, the addition of the IRE inhibitor significantly influenced sna/E-cad pathway which is essential in both p38 and JNK regulations. The results demonstrated an essential role of sna/E-cad in connecting the effects of carcinogens on UPR and MAPK regulations and the resultant metastasis.

 

Comments:

The study you described investigated the metastatic effects of three environmental carcinogens, namely 3,3',4,4',5-pentachlorobiphenyl (PCB126), perfluorooctanoic acid (PFOA), and cadmium chloride (CdCl2), using an in vivo model of the fruit fly Drosophila melanogaster. The researchers exposed the flies to these carcinogens for 8 days and examined their effects on tumor invasion, larval body weight, locomotion behavior, and gene expression pathways.

The results showed that exposure to PCB126, PFOA, and CdCl2 at a concentration of 1.0 mg/L significantly increased tumor invasion rates compared to the control group. The invasion rates were elevated by approximately 1.32-fold for PCB126, 1.33-fold for PFOA, and 1.29-fold for CdCl2. Additionally, the exposure to these carcinogens led to a decrease in larval body weight and impaired locomotion behavior.

The study also investigated the underlying molecular mechanisms involved in these metastatic effects. The researchers focused on two important signaling pathways, the MAPK (mitogen-activated protein kinase) pathway and the UPR (unfolded protein response) pathway. They found that PCB126, PFOA, and CdCl2 commonly disrupted the expression levels of target genes within these pathways.

To further explore the mechanisms, the researchers used inhibitors specific to key components of the MAPK and UPR pathways. They found that the addition of p38 inhibitor (SB203580), JNK inhibitor (SP600125), and IRE1 inhibitor (KIRA6) significantly abolished the metastatic effects of the carcinogens. This suggests that these inhibitors were able to mitigate the tumor invasion caused by PCB126, PFOA, and CdCl2.

Interestingly, the addition of the IRE1 inhibitor had a notable impact on the sna/E-cad pathway, which is important in both p38 and JNK regulation. This indicates that sna/E-cad plays a crucial role in connecting the effects of the carcinogens on UPR and MAPK regulations and the subsequent metastasis.

Overall, the study demonstrated that exposure to PCB126, PFOA, and CdCl2 in the fruit fly model resulted in increased tumor invasion rates and disrupted larval body weight and locomotion behavior. These effects were associated with alterations in the expression of genes within the MAPK and UPR pathways. Furthermore, the study highlighted the significance of the sna/E-cad pathway in linking the effects of these environmental carcinogens on UPR and MAPK signaling, thereby contributing to metastasis.