Inhibiting casein kinase 2 overcomes paclitaxel resistance in gastric cancer

Jung, Minkyu; Park, Kyu Hyun; Kim, Hyun Myong; Kim, Tae Soo; Zhang, Xianglan; Park, Sun Mi; Beom, Seung‐Hoon; Kim, Hyo Song; Cheong, Jae‐Ho; Chung, Hyun Cheol; Soong, John; Lin, Shu Hui; Rha, Sun Young

doi:10.1007/s10120-019-00971-7

Cited by 19 publications

(11 citation statements)

References 30 publications

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“…We were, therefore, concerned that systemic CK2 inhibition could exacerbate colitis. To address this, CK2 was inhibited using CX-4945, an orally bioavailable CK2 inhibitor (56)(57)(58)(59). CK2 inhibition neither accelerated nor attenuated DSS-induced weight loss ( Figure 6D) but caused a slight reduction in histopathology scores ( Figure 6E).…”

Section: Resultsmentioning

confidence: 99%

Inactivation of paracellular cation-selective claudin-2 channels attenuates immune-mediated experimental colitis in mice

Raju¹,

Shashikanth²,

Tsai³

et al. 2020

Journal of Clinical Investigation

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the larger cations tetramethylammonium, tetraethylammonium, or N-methyl-D-glucamine (Figure 1E). This size-selective permeability increase is characteristic of claudin-2 channel activity (14-16, 48-50), but does not exclude the possibility that other cation-selective pore-forming claudins, e.g., claudin-15 (10, 13, 22), contribute to IL-13-induced barrier loss in vivo. We therefore asked if claudin-2 was required for IL-13-induced barrier loss. Prior to IL-13 treatment, paracellular permeability was similar in Cldn2 +/+ and Cldn2-/mice, consistent with limited claudin-2 expression in adults. IL-13 treatment was not, however, able to increase paracellular permeability of small cations, including Na + and methylamine in Cldn2-/mice (Figure 1F). Claudin-2 is therefore necessary for IL-13-induced increases in intestinal pore pathway permeability. In order to determine if claudin-2 upregulation is sufficient to mediate the effects of IL-13 on intestinal cation permeability, transgenic mice expressing GFP-tagged mouse claudin-2 from the intestinal epithelium-specific villin (Vil1) promoter (Cldn2 Tg) were characterized (29). Total claudin-2 expression (the sum of endogenous and GFP-claudin-2) in these Cldn2 Tg mice was similar in distribution (Figure 1G) to that of IL-13-treated Cldn2 +/+ mice (Figure 1B) and increased 3.3-fold relative to Cldn2 +/+ mice that did not receive IL-13 (Figure 1, H and I). Moreover, transgenic GFPclaudin-2 expression selectively increased paracellular permeability of Na + , methylamine, and, to a lesser extent, ethylamine, in a manner that recapitulated the effect of IL-13 on Cldn2 +/+ mice (Figure 1J). Claudin-2 is, therefore, both necessary and sufficient to mediate IL-13-induced barrier loss in vivo. Transgenic claudin-2 expression exacerbates immune-mediated colitis. We have found that severity and duration of infectious colitis are reduced in these GFP-Cldn2 Tg mice (29). A study of similar transgenic mice expressing human claudin-2 from the same Vil1 promoter demonstrated that claudin-2 overexpression was also protective in DSS-induced, chemical colitis (41). Conversely, claudin-2 knockout exacerbated infectious and chemical colitis (29, 42). These data suggest that claudin-2-mediated pore pathway permeability increases may be adaptive, i.e., beneficial in IBD. To test this hypothesis, we compared severity of experimental IBD in immunodeficient Cldn2 Tg Rag1-/and Cldn2 +/+ Rag1-/mice using the well-established T cell transfer model (33, 51). Unexpectedly, disease was significantly more severe in Cldn2 Tg Rag1-/mice relative to Cldn2 +/+ Rag1-/mice. This was demonstrated by more extensive weight loss (Figure 2A) and greater disease activity (Figure 2B). Consistent with increased disease severity, leak (macromolecular) and unrestricted (epithelial damage) pathway permeabilities, measured as 4-kDa and 70-kDa dextran flux, respectively, were markedly greater in Cldn2 Tg Rag1-/mice relative to Cldn2 +/+ Rag1-/mice (Figure 2C and ref. 29). Colitis was associated with increased claudin-2 exp...

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Section: Resultsmentioning

confidence: 99%

Inactivation of paracellular cation-selective claudin-2 channels attenuates immune-mediated experimental colitis in mice

Raju¹,

Shashikanth²,

Tsai³

et al. 2020

Journal of Clinical Investigation

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“…The anti-tumour efficacy of combining CX-4945 and paclitaxel was also demonstrated in SNU-1 xenografted mice. Indeed, although both monotherapies were effective in delaying xenograft tumour growth and proliferation rates, the greatest tumour reduction was observed in mice that received the combined treatment [54].…”

Section: Cancers Of the Gastrointestinal Tractmentioning

confidence: 99%

Role of CK2 inhibitor CX-4945 in anti-cancer combination therapy – potential clinical relevance

et al. 2020

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Background Protein kinase CK2 inhibition has long been considered as an attractive anti-cancer strategy based on the following considerations: CK2 is a pro-survival kinase, it is frequently over-expressed in human tumours and its over-expression correlates with a worse prognosis. Preclinical evidence strongly supports the feasibility of this target and, although dozens of CK2 inhibitors have been described in the literature so far, CX-4945 (silmitasertib) was the first that entered into clinical trials for the treatment of both human haematological and solid tumours. However, kinase inhibitor monotherapies turned out to be effective only in a limited number of malignancies, probably due to the multifaceted causes that underlie them, supporting the emerging view that multi-targeted approaches to treat human tumours could be more effective. Conclusions In this review, we will address combined anti-cancer therapeutic strategies described so far which involve the use of CX-4945. Data from preclinical studies clearly show the ability of CX-4945 to synergistically cooperate with different classes of anti-neoplastic agents, thereby contributing to an orchestrated anti-tumour action against multiple targets. Overall, these promising outcomes support the translation of CX-4945 combined therapies into clinical anti-cancer applications.

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“…CK2 is implicated in the proliferation a wide variety of tumours, including gastric tumours [180], and to promote chemoresistance to anti-tumour agents such as paclitaxel [181]. CK2 inhibition by CX-4945 mitigates the Warburg effect [180], an effect possibly mediated at least in part via reduced phosphorylation of NNMT.…”

Section: Post-translational Modificationsmentioning

confidence: 99%

Nicotinamide N-Methyltransferase: An Emerging Protagonist in Cancer Macro(r)evolution

Parsons

Facey

2021

Biomolecules

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Nicotinamide N-methyltransferase (NNMT) has progressed from being considered merely a Phase II metabolic enzyme to one with a central role in cell function and energy metabolism. Over the last three decades, a significant body of evidence has accumulated which clearly demonstrates a central role for NNMT in cancer survival, metastasis, and drug resistance. In this review, we discuss the evidence supporting a role for NNMT in the progression of the cancer phenotype and how it achieves this by driving the activity of pro-oncogenic NAD+-consuming enzymes. We also describe how increased NNMT activity supports the Warburg effect and how it promotes oncogenic changes in gene expression. We discuss the regulation of NNMT activity in cancer cells by both post-translational modification of the enzyme and transcription factor binding to the NNMT gene, and describe for the first time three long non-coding RNAs which may play a role in the regulation of NNMT transcription. We complete the review by discussing the development of novel anti-cancer therapeutics which target NNMT and provide insight into how NNMT-based therapies may be best employed clinically.

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Inhibiting casein kinase 2 overcomes paclitaxel resistance in gastric cancer

Cited by 19 publications

References 30 publications

Inactivation of paracellular cation-selective claudin-2 channels attenuates immune-mediated experimental colitis in mice

Inactivation of paracellular cation-selective claudin-2 channels attenuates immune-mediated experimental colitis in mice

Role of CK2 inhibitor CX-4945 in anti-cancer combination therapy – potential clinical relevance

Nicotinamide N-Methyltransferase: An Emerging Protagonist in Cancer Macro(r)evolution

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