Drp1-JNK knockdown mitigates Scribble loss induced cell proliferation, metastasis and lethality phenotypes in Drosophila

Mitochondrial dynamics are emerging as master regulators for targeting several types of cancers, including breast cancer, cervical cancer, and hepatocellular carcinoma, for therapeutic intervention. Mitochondrial morphology, size, position and activity within cells is regulated by dynamic fission and fusion events. Dynamin-related protein 1 (Drp1) promotes mitochondrial fission and maintains mitochondrial homeostasis. Loss of Scrib is implicated in several human cancers wherein mitochondrial dysfunction leads to excessive cell proliferation and metastasis. However, the exact molecular mechanisms behind the Scrib loss induced dysregulation of mitochondrial dynamics in cancer progression remains obscure. Although the role of mitochondrial dynamics are being investigated in several types of cancers, but the role of Drp1- mediated fission event in regulating the maintenance of polarity of cells upon loss of Scrib function is elusive. In this study, for the first time, we blocked the function of Drp1 activity in Scrib knockdown induced metastasis cancer model by two ways, firstly, through genetic ablation of Drp1, and secondly by using mdivi-1, a Drp1 specific inhibitor. Genetic depletion of Drp1 expression (Drp1RNAi) in Scrib knockdown cells inhibits Metalloproteinase MMP1, reduces ROS production, restores apico-basal (A/B) cell polarity and enhances ATP production. Further to confirm role of Drp1 in regulation of cell polarity, we employed mdivi, a Drp1 specific inhibitor which has dose dependent effect in cell polarity regulation. This study also reveals that JNK inhibition (JNKRNAi) in Scrib abrogated cells mitigates the Drp1 expression and controls cell proliferation leading to restoration of mitochondrial morphology and epithelial cellpolarity. Our results highlight Drp1 as a key regulator in maintaining the apico-basal polarity of cells which gets affected upon loss of Scrib but Drp1-JNK downregulation effectively mitigates ScribRNAi associated cell proliferation, metastasis and pupal lethality phenotypes.