Cancer-Selective Targeting of the NF-κB Survival Pathway with GADD45β/MKK7 Inhibitors

Tornatore, Laura; Sandomenico, Annamaria; Raimondo, Domenico; Low, Caroline M. R.; Rocci, Alberto; Tralau-Stewart, Cathy; Capece, Daria; D’Andrea, Daniel; Bua, Marco; Boyle, Eileen M.; Duin, Mark van; Zoppoli, Pietro; Jaxa‐Chamiec, Albert; Thotakura, Anil K.; Dyson, Julian; Walker, Brian A.; Leonardi, Antonio; Sonneveld, Pieter; Morgan, Gareth J.; Palumbo, Antônio; Tramontano, Anna; Rahemtulla, Amin; Ruvo, Menotti; Franzoso, Guido

doi:10.1016/j.ccell.2014.11.021

Cited by 32 publications

(43 citation statements)

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“…An association between the upregulation and tumor resistance of NF-κB subfamilies and chemotherapy or radiotherapy has been shown for other cancers, such glioblastoma, multiple myeloma, hematological malignancies, and others (Bours et al, 2000;Braun et al, 2006;Friedmann-Morvinski et al, 2016;Garg, Hortobagyi, Aggarwal, Sahin, & Buchholz, 2003;F. Li & Sethi, 2010;Nakanishi & Toi, 2005;Tornatore et al, 2014). RelA/p65 and c-Rel overexpression is associated with poor survival of patients with B-cell lymphoma (L. M.…”

Section: Inhibition Of Nf-κbmentioning

confidence: 99%

Mechanisms of apoptosis modulation by curcumin: Implications for cancer therapy

Mortezaee

Salehi

Mirtavoos-Mahyari

et al. 2019

Journal Cellular Physiology

256

154

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Cancer incidences are growing and cause millions of deaths worldwide. Cancer therapy is one of the most important challenges in medicine. Improving therapeutic outcomes from cancer therapy is necessary for increasing patients’ survival and quality of life. Adjuvant therapy using various types of antibodies or immunomodulatory agents has suggested modulating tumor response. Resistance to apoptosis is the main reason for radioresistance and chemoresistance of most of the cancers, and also one of the pivotal targets for improving cancer therapy is the modulation of apoptosis signaling pathways. Apoptosis can be induced by intrinsic or extrinsic pathways via stimulation of several targets, such as membrane receptors of tumor necrosis factor‐α and transforming growth factor‐β, and also mitochondria. Curcumin is a naturally derived agent that induces apoptosis in a variety of different tumor cell lines. Curcumin also activates redox reactions within cells inducing reactive oxygen species (ROS) production that leads to the upregulation of apoptosis receptors on the tumor cell membrane. Curcumin can also upregulate the expression and activity of p53 that inhibits tumor cell proliferation and increases apoptosis. Furthermore, curcumin has a potent inhibitory effect on the activity of NF‐κB and COX‐2, which are involved in the overexpression of antiapoptosis genes such as Bcl‐2. It can also attenuate the regulation of antiapoptosis PI3K signaling and increase the expression of MAPKs to induce endogenous production of ROS. In this paper, we aimed to review the molecular mechanisms of curcumin‐induced apoptosis in cancer cells. This action of curcumin could be applicable for use as an adjuvant in combination with other modalities of cancer therapy including radiotherapy and chemotherapy.

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Section: Inhibition Of Nf-κbmentioning

confidence: 99%

Mechanisms of apoptosis modulation by curcumin: Implications for cancer therapy

Mortezaee

Salehi

Mirtavoos-Mahyari

et al. 2019

Journal Cellular Physiology

256

154

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“…Therefore, comprehensive sequence analysis in HCL may reveal additional mutated components of the NFkB-signalling pathway contributing to the pathology of HCL (Hatta et al, 2003). Aberrant NFkB activation and its particular treatment have been demonstrated in ABC-DLBCL and very recently in multiple myeloma (Staudt, 2010(Staudt, , 2013Nogai et al, 2013;Tornatore et al, 2014). Thus, therapeutic approaches applied for inhibition of NFkB-signalling may represent novel options for the treatment of HCL.…”

Section: Discussionmentioning

confidence: 99%

NFkB is activated by multiple mechanisms in hairy cell leukemia

Nagel

Ehrentraut

Meyer

et al. 2015

Genes Chromosomes & Cancer

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Hairy cell leukemia (HCL) is a rare chronic B-cell lymphoproliferative disorder of unclear pathogenesis. Recent studies have identified BRAF(V600E) mutations in most HCL patients, highlighting this abnormality as a molecular hallmark for this disease. Cell lines originating from HCL patients lack BRAF mutations but retain the typical piliferous morphology and the distinctive HCL immunophenotype, thus, constituting suitable tools for identifying alternative tumor genes and leukemic mechanisms in this malignancy. To this end, we integrated genomic and transcriptional profiling of the HCL cell line MLMA. The expression levels of genomically targeted genes were compared to four HCL control cell lines, thus, identifying 91 chromosomally deregulated genes. Gene set enrichment analysis of these indicted apoptosis, proliferation, and DNA damage response as altered processes. Accordingly, prominent target genes overexpressed in this cell line include ATM, BRAF, CDK6, CUTL1/CUX1, H2AFX, and REL. Treatment of MLMA with selective pharmacological inhibitors and specific siRNA-mediated gene knockdowns highlighted a central role for NFkB in their deregulation in HCL. Moreover, relevant expression profiling data from HCL and ABC-DLBCL cell lines display elevated NFkB-pathway activity when compared to GC-DLBCL equivalents. Finally, analysis of HCL patient samples in silico collectively supported the clinical significance of NFkB activation in this disease. In conclusion, we identified deregulated genes and multiple mechanisms underlying aberrantly activated NFkB-pathway in HCL. Therefore, NFkB may represent a B-cell specific hallmark of HCL and a promising novel therapeutic target, most notably in patients lacking BRAF mutations in this entity including variant HCL.

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“…Moreover, rather than inhibiting NF-B upstream signaling, selective targeting of NF-B downstream effects may be another attractive strategy to counteract lymphoma cell survival. For instance, a novel GADD45␤/MKK7 protein-protein interaction inhibitor promotes death of MM cells by preventing NF-B-dependent inhibition of pro-apoptotic MKK7/JNK signaling [133]. However, whereas JNK signaling was suggested to induce cell death in MM, JNK inhibitors exerted an anti-apoptotic role in ABC DLBCL [81].…”

Section: Conclusion and Therapeutic Implicationsmentioning

confidence: 97%