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A cell surface receptor for thyroid hormone that activates extracellular regulated kinase (ERK) 1/2 has been identified on integrin αvβ3. We have examined the actions of thyroid hormone initiated at the integrin on human NCI-H522 non-small cell lung carcinoma and NCI-H510A small cell lung cancer cells. At a physiologic total hormone concentration (10−7 M), T4 significantly increased proliferating cell nuclear antigen (PCNA) abundance in these cell lines, as did 3, 5, 3′-triiodo-L-thyronine (T3) at a supraphysiologic concentration. Neutralizing antibody to integrin αvβ3 and an integrin-binding Arg-Gly-Asp (RGD) peptide blocked thyroid hormone-induced PCNA expression. Tetraiodothyroacetic acid (tetrac) lacks thyroid hormone function but inhibits binding of T4 and T3 to the integrin receptor; tetrac eliminated thyroid hormone-induced lung cancer cell proliferation and ERK1/2 activation. In these estrogen receptor-α (ERα)-positive lung cancer cells, thyroid hormone (T4>T3) caused phosphorylation of ERα; the specific ERα antagonist ICI 182,780 blocked T4-induced, but not T3-induced ERK1/2 activation, as well as ERα phosphorylation, proliferating-cell nuclear antigen (PCNA) expression and hormone-dependent thymidine uptake by tumor cells. Thus, in ERα-positive human lung cancer cells, the proliferative action of thyroid hormone initiated at the plasma membrane is at least in part mediated by ERα. In summary, thyroid hormone may be one of several endogenous factors capable of supporting proliferation of lung cancer cells. Activity as an inhibitor of lung cancer cell proliferation induced at the integrin receptor makes tetrac a novel anti-proliferative agent.

Resveratrol is a naturally occurring trihydroxyl-diphenylethylene compound that has been shown experimentally to have beneficial effects in the treatment of cancer and cardiovascular disease. Resveratrol induces programmed cell death (apoptosis) in these cells and activates important signal transducing proteins including extracellular signal-regulated kinases (ERKs) 1 and 2 in cancer cells. Resveratrol also causes nuclear accumulation of the enzyme cyclooxygenase (COX)-2 and of the oncogene suppressor protein, p53. We have studied the molecular basis of the anticancer actions of resveratrol using human ovarian carcinoma (OVCAR-3) cells. Our findings include the following: (i) nuclear accumulation of COX-2 in resveratrol-treated cells is blocked by the ERK1/2 inhibitor, PD98059; (ii) an inhibitor of COX-2 activity, NS398, prevents accumulation of ERK1/2, COX-2, activated p53 and small ubiquitin-like modifier (SUMO-1) in the nucleus; (iii) apoptosis, quantitated by nucleosome enzyme-linked immunosorbent assay and the nuclear abundance of the pro-apoptotic protein, BcL-xs, were inhibited by NS398. This finding implicates nuclear COX-2 in p53-mediated apoptosis induced by resveratrol. Sumoylation is important to stabilization of p53 and a COX-2-SUMO-1 interaction suggests sumoylation of COX-2 in resveratrol-treated cells and (iv) chromatin immunoprecipitation studies showed binding of induced nuclear COX-2 to the promoter region of PIG3 and Bax, pro-apoptotic gene targets of transcriptionally active p53. Nuclear accumulation of activated ERK1/2 and sumolyated COX-2 are essential to resveratrol-induced pSer-15-p53-mediated apoptosis in human ovarian cancer cells.

Thyroid hormone induces tumor cell and blood vessel cell proliferation via a cell surface receptor on heterodimeric integrin αvβ3. We investigated the role of thyroid hormone-induced internalization of nuclear integrin αv monomer. Physiological concentration of thyroxine (free T4, 10(-10) M), but not 3,5,3'-triiodo-l-thyronine (T3), induced cellular internalization and nuclear translocation of integrin αv monomer in human non-small-cell lung cancer (H522) and ovarian carcinoma (OVCAR-3) cells. T4 did not complex with integrin αv monomer during its internalization. The αv monomer was phosphorylated by activated ERK1/2 when it heterodimerized with integrin β3 in vitro. Nuclear αv complexed with transcriptional coactivator proteins, p300 and STAT1, and with corepressor proteins, NCoR and SMRT. Nuclear αv monomer in T4-exposed cells, but not integrin β3, bound to promoters of specific genes that have important roles in cancer cells, including estrogen receptor-α, cyclooxygenase-2, hypoxia-inducible factor-1α, and thyroid hormone receptor β1 in chromatin immunoprecipitation assay. In summary, monomeric αv is a novel coactivator regulated from the cell surface by thyroid hormone for the expression of genes involved in tumorigenesis and angiogenesis. This study also offers a mechanism for modulation of gene expression by thyroid hormone that is adjunctive to the nuclear hormone receptor (TR)-T3 pathway.