Inhibition of growth and survival of human head and neck squamous cell carcinoma cells by curcumin via modulation of nuclear factor‐κB signaling

Abstract

Key words: HNSCC; NF-B; IB␣; IKK; apoptosis; MMP-9; cyclin D1; COX-2Head and neck squamous cell carcinoma (HNSCC) includes epithelial malignancies that arise from the mucosal lining of the oral cavity, oropharynx, nose and pernasal sinuses, hypopharynx and larynx. These cancers occur more than twice as often in men as in women. 1 HNSCC are among the most morbid of human cancers and affect annually nearly 500,000 people world-wide and approximately 40,000 cases in the United States, making it the sixth most common cancer type.Cigarette-smoking, tobacco-chewing and betel or areca nut chewing are environmental factors associated with increased risk of developing HNSCC. [1][2][3] Despite standard treatment strategies that involve surgery, radiotherapy or chemotherapy, the survival rate of patients with this cancer has remained poor. A total of 30 -50% of patients develop local or regional recurrence, and an increasing number of patients are developing distant metastases. 4 Another 10 -40% patients develop second primary tumors of the aerodigestive tract as a result of field cancerization. 5 Preventing cancer by inhibiting carcinoma before invasive tumors develop is a promising strategy, but current strategies have limited efficacy and documented toxicity. 6,7 Modulating the expression of proinflammatory and proangiogenic factors associated with aggressive tumor growth and decreased survival of patients with HNSCC is one avenue that holds potential. 8 -12 Several of the cytokines expressed by HNSCC are regulated by the nuclear transcription factor NF-B. NF-B consists of a group of 5 proteins: c-Rel, RelA (p65), Rel B, NF-B1 (p50 and p105) and NF-B2 (p52). 13 In resting state, NF-B is sequestered in the cytoplasm through its tight association with a specific inhibitory proteins. These proteins are inhibitors of NF-B (IB) and belong to a gene family consisting of IB␣, IB␤, IB⑀, IB␥, Bcl-3, p100 and p105. 13 On activation by agents such as TNF, the IB␣ is phosphorylated at serine residue 32 and 36, ubiquitinated at lysine residue 21 and 22 and degraded through the proteasomal pathway, exposing the nuclear localization signals on the p50 -p65 heterodimer. p65 then undergoes phosphorylation, leading to nuclear translocation and binding to a specific sequence in DNA. This results in gene transcription. The phosphorylation of IB␣ is catalyzed by the IB␣ kinase (IKK) consisting of IKK-␣, IKK-␤ and IKK-␥ (also called NF-B essential modulator (NEMO). 13 Gene deletion studies have indicated that IKK-␤ is essential for NF-B activation by TNF. 14 -16 IKK-␣ deletion, however, has no effect on NF-B activation by most agents. Determining which kinase induces the phosphorylation of p65 is controversial but the role of PKA, casein kinase II, glycogen synthase kinase-3␤, IKK-␣ and IKK-␤ have been implicated. [17][18][19][20][21][22][23] It has been shown that the phosphorylation of p65 at serine 529 is required for TNF-induced transcriptional activity of NF-B. 24 NF-B is activated by a wide variety of agents including various carcinog...

Evidence that TNF-TNFR1-TRADD-TRAF2-RIP-TAK1-IKK pathway mediates constitutive NF-κB activation and proliferation in human head and neck squamous cell carcinoma

“…Furthermore, suppression of TNF cell signaling pathway in HNSCC cells downregulated the constitutively active NF-kB, and proliferation of cells (Figure 8). Using DNA binding and immunocytochemical analysis, we and others have previously shown that NF-kB is constitutively active in HNSCC Aggarwal et al, 2004). Our results, for the first time, now demonstrate that HNSCC cells express transcriptionally active NF-kB.…”

“…More recently, constitutively active NF-kB activation has also been found in cancer patients and shown to correlate with prognosis of the disease (Buchholz et al, 2005;Izzo et al, 2006). Work from our laboratory and others have shown that NF-kB is constitutively active in head and neck squamous cell carcinoma (HNSCC) Aggarwal et al, 2004), and play a critical role in the proliferation of the tumor cells LoTempio et al, 2005). Additionally, HNSCC have been shown to produce inflammatory cytokines such as interleukin (IL)-6 and IL-8 which are also regulated by NF-kB (Wolf et al, 2001;Wang et al, 2002;Thomas et al, 2004).…”

Overexpression of phosphorylated nuclear factor-kappa B in tonsillar squamous cell carcinoma and high-grade dysplasia is associated with poor prognosis

“…33 Curcumin represents another potential therapeutic option in squamous cell carcinoma of the tonsil by virtue of its ability to inhibit the growth and survival of human head and neck squamous cell carcinoma cells via modulation of NF-kB signaling. 34 The latter is accomplished through curcumin's ability to abrogate I-kB alpha kinase (IKK), which is needed for NF-kB activation. Curcumin is also attractive because of its apparent use and relative pharmacological safety in humans.…”

Preclinical assessment of curcumin as a potential therapy for B‐CLL

“…In studies of the myeloid cell line ML-1a, Singh and Aggarwal reported that curcumin inhibited IkBa phosphorylation, degradation, and NF-kB translocation induced by a diverse range of stimuli including TNF, hydrogen peroxide, and phorbol esters [2]. Subsequent studies confirmed curcumininduced inhibition of NF-kB translocation in multiple cell types, including colon [3], gastric [4], pancreatic [5], and squamous epithelial tumor cell lines [6] as well as B-cell lymphoma and multiple myeloma cell lines [7,8]. Although the precise mechanism by which NF-kB translocation is inhibited remains unclear, Plummer et al demonstrated that curcumin reduced NF-kB translocation in HEK293 cells transfected with NIK, IKKa, or IKKb kinases [3].…”