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    • Mitochondrial is the main source for ROS and

    2022-03-14

    Mitochondrial is the main source for ROS and ATP generation, and the loss of mitochondrial membrane potential is involved in the alteration of mitochondrial metabolism and mitochondrial failure-induced cell death [33,34]. In this study, we showed that upregulated ZNF32 sustained mitochondrial membrane potential and facilitated ATP production in detached HCC cells, suggesting that ZNF32 protected detached HCC carboxypeptidase a from anoikis by modulating mitochondrial function. In support of this, expression of SOD2, a mitochondrial protein that reduces oxidative stress-induced mitochondrial impairment caused by respiratory chain leak, was increased in more advanced and higher grade mammary tumors and positively correlated with metastasis of breast cancer cells [35]. Furthermore, the elevated expressions of ZNF32 in detached HCC cells were significantly inhibited by NAC or GSH treatment. Our previous study demonstrated that the transcription of ZNF32 was precisely regulated by SP1 upon oxidants treatment [15]. These results suggest that ZNF32 may act as a sensor of intracellular ROS levels that maintains redox homeostasis under oxidative stress. FAK, a broadly expressed non-receptor tyrosine kinase which transduces signals from integrins, growth and hormonal factors, plays a critical role in many fundamental biological processes and functions, including cell adhesion, migration, proliferation and survival [36,37]. Src was found to induce the FAK phosphorylation at Y397, leading to the activation of FAK [22,38]. In the present study, we found that ZNF32 overexpression promoted the phosphorylations of Src and FAK, whereas knockdown of ZNF32 resulted in inactivation of Src and FAK after detachment. In line with our observation, several studies reported that the activation of Src triggered downstream pro-survival pathways to confer anoikis resistance, thus promoted tumor growth and metastasis [39,40]. In contrast, the Src kinase inhibitor PP2 and FAK inhibitor Y15 treatment significantly inhibited anchorage-independent growth of ZNF32-overexpressing HCC cells. Therefore, our data indicate that the ZNF32 overexpression activates Src, which in turn promotes phosphorylation of FAK, and ultimately leading to anoikis resistance in HCC.
    Conflicts of interest
    Acknowledgements This work was supported by the National High Technology Research and Development Program of China (863 Program, 2015AA020306).
    Introduction Cell survival and apoptosis are complex processes involving multiple extracellular cues and intracellular signaling events that may promote or reduce cellular death in a context dependent manner [1,2]. Stimulatory growth factor receptor signaling in response to various growth factors is the major determinant of cell survival [3,4]. However, adherent cells also require pro-survival signaling from the extracellular matrix, mediated primarily through integrins [1,5]. Cross-talk between integrins and growth factor receptors facilitates triggering of downstream pathways, which regulate an elaborate apparatus of anti- and pro-apoptotic proteins [6,7]. The most well-studied effecter of integrin-mediated adhesion signaling is the focal adhesion kinase (FAK) [8,9]. Activation of FAK, it's tyrosine kinase function and ability to form complexes with numerous cellular partners, links upstream adhesion-associated events to multiple cellular processes [10]. In cell-survival, FAK is known to promote adhesion-induced activation of the AKT pathway that suppresses pro-apoptotic BCL2 family proteins [11]. Extracellular signal-regulated kinase (ERK) family proteins are also phosphorylated and activated in response to cell adhesion [12,13]. In addition to integrin-associated ERK1/2 activation, adhesion-mediated p38 MAPK and ERK5 signaling-cascades are also prominently observed in cell lines as well as primary cells of mouse and human origin [14,15]. ERK5 signaling can be triggered in response to diverse stimulants including mitogens, cytokines and stress [16]. The immediate up-stream determinant of ERK5 activation is MEK5 and MEK5/ERK5 pathway is known to influence cell proliferation, survival, migration and differentiation [16,17]. In endothelial cells, VEGF can induce MEK5/ERK5 signaling cascade, which is essential for angiogenesis and maintenance of vasculature [18]. Enhanced ERK5 signaling plays an important part in driving angiogenesis in tumors and has been explored as a target in cancer therapy [19,20]. In addition to regulating angiogenesis, ERK5 is implicated in metastasis, cell cycle progression and inhibition of tumor suppressors in cancers [17,21,22]. Altered ERK5 expression has been also reported in some cancers including prostate and hepatocellular carcinoma [22,23]. In breast cancer, altered regulation and over-activation of MEK5/ERK5 signaling is associated with poor prognosis [24,25]. Adhesion-induced ERK5 activation has been reported in MDA-MB231 and PC3 cancer cell lines [15,26]. In these cells intergrin-mediated MEK5/ERK5 signaling was found to be FAK-dependent [15]. Interestingly, FAK is also a target of ERK5 kinase activity and Ser 910 of FAK is phosphorylated by ERK5 in response to phorbol myristate acetate (PMA) stimulation [27,28].