The IKKα-dependent non-canonical pathway of NF-κB activation is constitutively active and modulates progression-related functions in a subset of human melanomas

The inhibitory kappa B kinases (IKKs) and IKK related kinases are crucial regulators of the pro-inflammatory transcription factor, nuclear factor kappa B (NF-κB). The dysregulation in the activities of these kinases has been reported in several cancer types. These kinases are known to regulate survival, proliferation, invasion, angiogenesis, and metastasis of cancer cells. Thus, IKK and IKK related kinases have emerged as an attractive target for the development of cancer therapeutics. Several IKK inhibitors have been developed, few of which have advanced to the clinic. These inhibitors target IKK either directly or indirectly by modulating the activities of other signaling molecules. Some inhibitors suppress IKK activity by disrupting the protein-protein interaction in the IKK complex. The inhibition of IKK has also been shown to enhance the efficacy of conventional chemotherapeutic agents. Because IKK and NF-κB are the key components of innate immunity, suppressing IKK is associated with the risk of immune suppression. Furthermore, IKK inhibitors may hit other signaling molecules and thus may produce off-target effects. Recent studies suggest that multiple cytoplasmic and nuclear proteins distinct from NF-κB and inhibitory κB are also substrates of IKK. In this review, we discuss the utility of IKK inhibitors for cancer therapy. The limitations associated with the intervention of IKK are also discussed.

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“…One study assessed the role of IKKα in melanoma patients [105]. The expression of IKKα and overall activation of NF-κB were heterogeneous.…”

Section: Ikk Inhibition By Peptides/bio-molecules-another Approach For Suppressingmentioning

confidence: 99%

“…• IKKα siRNA: Reduced doxorubicin-induced NF-κB activation, constitutive and TNFα-stimulated expression of CXCL8 and ICAM-1, and cell migration in melanoma cells [105].…”

Section: Abbreviationsmentioning

confidence: 99%

Targeting IκappaB kinases for cancer therapy

Awasthee

Rai

Chava

et al. 2019

Seminars in Cancer Biology

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“…MicroRNAs (miRNAs/miRs) are an important molecular mediator of cell genetic changes, and are directly or indirectly associated with the occurrence and development of a number (6)(7)(8)(9)(10). Previous studies have indicated that Tudor-SN has a close association with lipid metabolism, and that the expression of lipoprotein in liver cells can be affected through adjustment of lipid metabolism-associated genes (11,12).…”

Section: Introductionmentioning

confidence: 99%

Tudor‑staphylococcal nuclease regulates the expression and biological function of alkylglycerone phosphate synthase via nuclear factor‑κB and microRNA‑127 in human glioma U87MG cells

Zhang

Jia

et al. 2018

Oncol Lett

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Abstract. Glioma is one of the malignant tumor types detrimental to human health; therefore, it is important to find novel targets and therapeutics for this tumor. The downregulated expression of Tudor-staphylococcal nuclease (SN) and alkylglycerone phosphate synthase (AGPS) can decrease cancer malignancy, and the overexpression of them can the increase viability and migration potential of various tumor cell types; however, the role of AGPS in the proliferation and migration of glioma, and the association of Tudor-SN and AGPS in human glioma is not clear. In the present study, it was determined that AGPS silencing suppressed the proliferation and migration potential of glioma U87MG cells, and suppressed the expression of the circular RNAs circ-ubiquitin-associated protein 2, circ-zinc finger protein 292 and circ-homeodomain-interacting protein kinase 3, and the long non-coding RNAs H19 imprinted maternally expressed transcript (non-protein coding), colon cancer-associated transcript 1 (non-protein coding) and hepatocellular carcinoma upregulated long non-coding RNA. Furthermore, Tudor-SN silencing suppressed the expression of AGPS; however, nuclear factor (NF)-κB and microRNA (miR)-127 retrieval experiments partially reduced the expression of AGPS. Additionally, it was determined that Tudor-SN silencing suppressed the activity of the mechanistic target of rapamycin (mTOR) signaling pathway, and NF-κB and miR-127 retrieval experiments partially reduced the activity of mTOR. Therefore, it was considered that NF-κB and miR-127 may be the mediators of Tudor-SN-regulated AGPS via the mTOR signaling pathway. These results improve on our knowledge of the mechanisms underlying Tudor-SN and AGPS in human glioma. IntroductionGliomas are a type of tumor formed by neoplastic transformation of neural stem cells, progenitor cells and differentiated glial cells, including astrocytes, oligodendrocytes and ependymal cells (1). Neoplastic cells may spread diffusely to normal brain tissues and damage normal neurological functions, which is the reason why malignant gliomas are detrimental to human health (2). In China, gliomas constitute 44.69% of primary intracranial tumors and 1-3% of generalized malignancies (3). According to the World Health Organization, malignant glioma causes the second highest amount of mortalities in sufferers <34 years old, and the third highest amount of mortalities in sufferers aged 35-54 years old (4). It is estimated that the survival time of the majority of glioma sufferers is ~1 year. Although there are currently various treatments available, including excision, chemotherapy and radiotherapy, the characteristic of strong invasiveness has severely influenced the effectiveness of glioma treatment.MicroRNAs (miRNAs/miRs) are an important molecular mediator of cell genetic changes, and are directly or indirectly associated with the occurrence and development of a number

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