NIK/MAP3K14 Regulates Mitochondrial Dynamics and Trafficking to Promote Cell Invasion

Abstract

SUMMARY Although the role of NF-κB-inducing kinase (NIK) in immunity is well established, its relevance in cancer is just emerging. Here we describe novel functions for NIK in regulating mitochondrial dynamics and motility to promote cell invasion. We show that NIK is localized to mitochondria in cancer cell lines, ex vivo tumor tissue, and mouse embryonic fibroblasts (MEFs). NIK promotes mitochondrial fission, velocity, and directional migration, resulting in subcellular distribution of mitochondria to the periphery of migrating cells. Moreover, NIK is required for recruitment of Drp1 to mitochondria, forms a complex with Drp1, and regulates Drp1 phosphorylation at Ser-616 and dephosphorylation at Ser-637. Consistent with a role for NIK in regulating mitochondrial dynamics, we demonstrate that Drp1 is required for NIK-dependent, cytokine-induced invasion. Importantly, using MEFs, we demonstrate that the established downstream mediators of NIK signaling, IκB kinase α/β (IKKα/β) and NF-κB, are not required for NIK to regulate cell invasion, Drp1 mitochondrial localization, or mitochondrial fission. Our results establish a new paradigm for IKK-independent NIK signaling and significantly expand the current dogma that NIK is predominantly cytosolic and exclusively regulates NF-κB activity. Overall, these findings highlight the importance of NIK in tumor pathogenesis and invite new therapeutic strategies that attenuate mitochondrial dysfunction through inhibition of NIK and Drp1.

Mitochondrial Dynamics in Regulating the Unique Phenotypes of Cancer and Stem Cells

“…Mechanistically, NF-κB-inducing kinase (NIK) seems to regulate DRP1 involvement in cell migration in multiple cancer types, including glioma, breast cancer, and pancreatic cancer (Jung et al, 2016). Loss of NIK greatly reduces invasive activity and causes congregation of mitochondria around the nucleus as opposed to their normal, predominantly anterograde movement toward the leading edge of migrating cancer cells.…”

The role of mitochondria in axon development and regeneration

“…Increased expression and activation of Drp1 in metastatic breast cancer cells results in smaller more motile mitochondria that, as evidenced by interfering with Drp1 function, promote the cell's metastatic potential (Zhao et al, ). NF‐κB‐inducing kinase has similarly been found to activate Drp1 and thereby promote mitochondria redistribution to the leading edges of migrating cancer cells (Jung et al, ). Invadopodia are protrusive structures used by migrating cancer cells to penetrate tissues and establish new sites of tumor growth (Seano and Primo, ).…”

The mitochondrial dynamics in cancer and immune-surveillance

“…Moreover, SNPH downregulation correlates also with poor survival prognosis in colon and lung adenocarcinoma patients [76]. Recently, it has been shown that NF-κB-inducing kinase (NIK) localizes at OMM in both MEFs and cancer cell lines where it interacts with Drp1, by promoting its translocation and activation; this favours fragmented mitochondria redistribution to lamellipodia and sustains high-speed cell migration [77]. Such a role is independent from the downstream mediators of NIK signalling [77].…”

“…Recently, it has been shown that NF-κB-inducing kinase (NIK) localizes at OMM in both MEFs and cancer cell lines where it interacts with Drp1, by promoting its translocation and activation; this favours fragmented mitochondria redistribution to lamellipodia and sustains high-speed cell migration [77]. Such a role is independent from the downstream mediators of NIK signalling [77]. Therefore, it seems that the metastatic potential of cancer cells often correlates with increased Drp1 or decreased Mfns activities, as shown -respectively, for breast cancer and glioma metastasis [71,74], and gastric cancer cells [71].…”