Inhibition of growth and survival of human head and neck squamous cell carcinoma cells by curcumin via modulation of nuclear factor-kappaB signaling.
Increased expression of proinflammatory and proangiogenic factors are associated with aggressive tumor growth and decreased survival of patients with head and neck squamous cell carcinoma (HNSCC). In as much as genes that are regulated by nuclear factor NF-kappaB suppress apoptosis, induce proliferation, and mediate inflammation, angiogenesis and tumor metastasis, agents that suppress NF-kappaB activation have potential as treatment for various cancers including HNSCC. We demonstrate that all HNSCC cell lines expressed constitutively active NF-kappaB and IkappaBalpha kinase (IKK), which is needed for NF-kappaB activation. Treatment of MDA 686LN cells with curcumin (diferuloylmethane), a pharmacologically safe chemopreventive agent, inhibited NF-kappaB activation through abrogation of IKK. As a result expression of various cell survival and cell proliferative genes including Bcl-2, cyclin D1, IL-6, COX-2 and MMP-9 was suppressed. This, in turn, inhibits proliferation of all HNSCC cell lines, arrests cell cycle in G1/S phase (MDA 686LN) and induces apoptosis as indicated by upstream and downstream caspase activation, PARP cleavage, annexin V staining in MDA 686LN cells. Suppression of NF-kappaB by cell-permeable p65-based peptide and NBD peptide also inhibited the proliferation and induced apoptosis in these cells. Our results indicate that curcumin is a potent inhibitor of cell proliferation and an inducer of apoptosis in HNSCC through suppression of IKK-mediated NF-kappaB activation and of NF-kappaB-regulated gene expression.
Aggarwal
Sita
S
Cytokine Research Laboratory, Department of Bioimmunotheraphy, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA. aggarwal@mdanderson.org
Takada
Yasunari
Y
Singh
Sujay
S
Myers
Jeffrey N
JN
Aggarwal
Bharat B
BB
D000818:Animals; D000906:Antibodies; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology*; D020169:Caspases / Q000096:biosynthesis / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D003474:Curcumin / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D051550:I-kappa B Kinase; D016328:NF-kappa B / Q000494:pharmacology*; D009362:Neoplasm Metastasis; D017346:Protein Serine-Threonine Kinases / Q000494:pharmacology; D011817:Rabbits; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D000906:Antibodies; D000970:Antineoplastic Agents; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D020169:Caspases; D003474:Curcumin