HIF1α and NFkB are two transcription factors very frequently activated in tumors and involved in tumor growth, progression, and resistance to chemotherapy. In fact, HIF1α and NFkB together regulate transcription of over a thousand genes that, in turn, control vital cellular processes such as adaptation to the hypoxia, metabolic reprograming, inflammatory reparative response, extracellular matrix digestion, migration and invasion, adhesion, etc. Because of this wide involvement they could control in an integrated manner the origin of the malignant phenotype. Interestingly, hypoxia and inflammation have been sequentially bridged in tumors by the discovery that alarmin receptors genes such as RAGE, P2X7, and some TLRs, are activated by HIF1α; and that, in turn, alarmin receptors strongly activate NFkB and proinflammatory gene expression, evidencing all the hallmarks of the malignant phenotype. Recently, a large number of drugs have been identified that inhibit one or both transcription factors with promising results in terms of controlling tumor progression. In addition, many of these molecules are natural compounds or off-label drugs already used to cure other pathologies. Some of them are undergoing clinical trials and soon they will be used alone or in combination with standard anti-tumoral agents to achieve a better treatment of tumors with reduction of metastasis formation and, more importantly, with a net increase in survival. This review highlights the central role of HIF1α activated in hypoxic regions of the tumor, of NFkB activation and proinflammatory gene expression in transformed cells to understand their progression toward malignancy. Different molecules and strategies to inhibit these transcription factors will be reviewed. Finally, the central role of a new class of deacetylases called Sirtuins in regulating HIF1α and NFkB activity will be outlined.

SummaryThe immunosuppressant hormone dexamethasone (Dex) interferes with T cell-specific signals activating the enhancer sequences directing interleukin 2 (IL-2) transcription. We report that the Dex-dependent downregulation of 12-O-tetradecanoyl-phorbo1-13-acetate (TPA) and calcium ionophore-induced activity of the I1,2 enhancer are mediated by glucocorticoid receptor (GR) via a process that requires intact NH2-and COOH-terminal and DNA-binding domains. Functional analysis of chloramphenicol acetyltransferase (CAT) vectors containing internal ddetions of the -317 to + 47 bp I1,2 enhancer showed that the GR-responsive elements mapped to regions containing nuclear factor of activated T cells protein (NFAT) (-279 to -263 bp) and AP-1 (-160 to -150 bp) motifs. The AP-1 motif binds TPA and calcium ionophore-induced nuclear factor(s) containing los protein. TPA and calcium ionophore-induced transcriptional activation of homooligomers of the NFAT dement were not inhibited by Dex, while AP-1 motif concatemers were not stimulated by TPA and calcium ionophore. When combined, NFAT and AP-1 motifs significantly synergized in directing CAT transcription. Such a synergism was impaired by specific mutations affecting the tram-acting factor binding to either NFAT or AP-1 motifs. In spite of the lack of hormone regulation of isolated c/s dements, TPA/calcium ionophore-mediated activation of CAT vectors containing a combination of the NFAT and the AP-1 motifs became suppressible by Dex. Our results show that the IL-2-AP-1 motif confers GR sensitivity to a flanking region containing a NFAT dement and suggest that synergistic cooperativity between the NFAT and AP-1 sites allows GR to mediate the Dex inhibition of I1`2 gene transcription. Therefore, a Dex-modulated second level of II:2 enhancer regulation, based on a combinatorial modular interplay, appears to be present.

The oncogenic effects of epidermal growth factor (EGF) have long been established. EGF receptor (EGFr) is overexpressed in many types of tumors and constitutes a target for cancer treatment. The pituitary gland is a target of EGF action and it is very likely that EGFr plays a role in pituitary tumor formation and progression. However, there is a controversy in the literature concerning EGFr expression in the different types of pituitary adenomas. In the present study we investigated the expression pattern of the wild type EGFr (EGFrWT) and the constitutively active variant III (EGFrvIII) at the mRNA and protein levels in a large series of pituitary tumors. EGFrWT was found in a high percentage of hormone-secreting tumors, but only in a small fraction of non-functioning pituitary adenomas, while no expression of the EGFrvIII could be detected by nested RT-PCR in any tumor. Among the hormone-secreting adenomas, the highest incidence of EGFr expression was found in Cushing's pituitary adenomas. Furthermore, immunohistochemistry for the phosphorylated EGFr revealed the presence of activated EGFr in most Cushing's adenomas, compared with most pituitary adenomas. Taking into account that downregulation of p27/Kip1 plays a significant role in corticotrope tumorigenesis and that EGFr mitogenic signaling results in decreased p27/Kip1, we searched for a correlation between EGFr expression and p27/Kip1 levels in corticotropinomas. Low p27/Kip1 immunoreactivity was observed in corticotropinomas expressing EGFr. On the other hand, somatotropinomas expressing EGFr had high p27/Kip1 immunoreactivity. These data suggest a corticotrope-specific phenomenon and indicate that EGFr may have a role in the unbalanced growth of corticotrope tumoral cells.

These data support the evidence that molecules typical of the innate immune system, similar to that of activated leukocytes, are produced by prostate epithelial cells and that their expression is up-regulated in malignant cells. We suggest that the observed pro-inflammatory and repair process activation may represent an important molecular mechanism in the progression of prostate cancer.