Drp1-JNKknockdown mitigates Scribble loss induced cell proliferation, metastasis and lethality phenotypes inDrosophila

Abstract

AbstractMitochondrial 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 ofScribis implicated in several human cancers wherein mitochondrial dysfunction leads to excessive cell proliferation and metastasis. However, the exact molecular mechanisms behind theScribloss 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 ofDrp1- mediated fission event in regulating the maintenance of polarity of cells upon loss ofScribfunction is elusive. In this study, for the first time, we blocked the function ofDrp1activity inScribknockdown induced metastasis cancer model by two ways, firstly, through genetic ablation ofDrp1,and secondly by using mdivi-1, aDrp1specific inhibitor. Genetic depletion ofDrp1expression (Drp1RNAi) inScribknockdown cells inhibits MetalloproteinaseMMP1, 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 thatJNKinhibition (JNKRNAi) inScribabrogated cells mitigates theDrp1expression and controls cell proliferation leading to restoration of mitochondrial morphology and epithelial cellpolarity. Our results highlightDrp1as a key regulator in maintaining the apico-basal polarity of cells which gets affected upon loss ofScribbutDrp1-JNKdownregulation effectively mitigatesScribRNAiassociated cell proliferation, metastasis and pupal lethality phenotypes.