Pancreatic ductal adenocarcinoma (PDAC) is responsible for 7.3% of all cancer deaths. Even though there is a steady increase in patient survival for most cancers over the decades, the patient survival rate for pancreatic cancer remains low with current therapeutic strategies. The Wnt/β-catenin pathway controls the maintenance of somatic stem cells in many tissues and organs and is implicated in pancreatic carcinogenesis by regulating cell cycle progression, apoptosis, epithelial-mesenchymal transition (EMT), angiogenesis, stemness, tumor immune microenvironment, etc. Further, dysregulated Wnt has been shown to cause drug resistance in pancreatic cancer. Although different Wnt antagonists are effective in pancreatic patients, limitations remain that must be overcome to increase the survival benefits associated with this emerging therapy. In this review, we have summarized the role of Wnt signaling in pancreatic cancer and suggested future directions to enhance the survival of pancreatic cancer patients.

Background: IL-8 promotes angiogenesis and metastasis in ovarian cancer. Results: Proteasome inhibition induces specific recruitment of IKK␤, EGR-1, and S536P-p65 to the IL-8 promoter. Conclusion:The increased IKK␤, EGR-1, and S536P-p65 recruitment results in the increased IL-8 expression and release in ovarian cancer cells. Significance: The BZ-increased IL-8 release may be responsible for the BZ-limited effectiveness in ovarian cancer treatment.

Edited by Alex TokerAMP-activated protein kinase (AMPK) is an energy sensor and master regulator of metabolism. AMPK functions as a fuel gauge monitoring systemic and cellular energy status. Activation of AMPK occurs when the intracellular AMP/ATP ratio increases and leads to a metabolic switch from anabolism to catabolism. AMPK phosphorylates and inhibits acetyl-CoA carboxylase (ACC), which catalyzes carboxylation of acetyl-CoA to malonyl-CoA, the first and rate-limiting reaction in de novo synthesis of fatty acids. AMPK thus regulates homeostasis of acetylCoA, a key metabolite at the crossroads of metabolism, signaling, chromatin structure, and transcription. Nucleocytosolic concentration of acetyl-CoA affects histone acetylation and links metabolism and chromatin structure. Here we show that activation of AMPK with the widely used antidiabetic drug metformin or with the AMP mimetic 5-aminoimidazole-4-carboxamide ribonucleotide increases the inhibitory phosphorylation of ACC and decreases the conversion of acetyl-CoA to malonyl-CoA, leading to increased protein acetylation and altered gene expression in prostate and ovarian cancer cells. Direct inhibition of ACC with allosteric inhibitor 5-(tetradecyloxy)-2-furoic acid also increases acetylation of histones and non-histone proteins. Because AMPK activation requires liver kinase B1, metformin does not induce protein acetylation in liver kinase B1-deficient cells. Together, our data indicate that AMPK regulates the availability of nucleocytosolic acetyl-CoA for protein acetylation and that AMPK activators, such as metformin, have the capacity to increase protein acetylation and alter patterns of gene expression, further expanding the plethora of metformin's physiological effects.Acetylation is one of the epigenetic post-translational modifications of histones; it affects chromatin structure and regulates diverse cellular functions, such as gene expression, DNA replication and repair, and cellular proliferation (1, 2). Acetylation and deacetylation of chromatin histones, mediated by histone acetyltransferases (HATs) 3 and histone deacetylases (HDACs), respectively, represent the major mechanisms for epigenetic gene regulation. The dynamic balance between histone acetylation and deacetylation, mediated by the activities of HATs and HDACs, is stringently regulated in healthy cells but is often dysregulated in cancer (3, 4).Histone acetylation depends on intermediary metabolism for supplying acetyl-CoA in the nucleocytosolic compartment (5). In mammalian cells, the nucleocytosolic enzyme ATP-citrate lyase is the major source of acetyl-CoA for histone acetylation (6). Another mechanism for generation of acetyl-CoA in the nucleus involves translocation of pyruvate dehydrogenase from mitochondria to the nucleus (7). In yeast, global histone acetylation depends on nucleocytosolic acetyl-CoA produced by acetyl-CoA synthetase (5). In both yeast and mammalian cells, the nucleocytosolic acetyl-CoA is the link among cellular energy, carbon metabolism, histone acetylation, ...

No abstract

Histone acetyltransferases (HATs) and histone deacetylases (HDACs) counteract with each other to regulate gene expression by altering chromatin structure. Aberrant HDAC activity was reported in many human diseases including wide range of cancers, viral infections, cardiovascular complications, auto-immune diseases and kidney diseases. HDAC inhibitors are small molecules designed to block the malignant activity of HDACs. Chemokines and cytokines control inflammation, immunological and other key biological processes and are shown to be involved in various malignancies. Various HDACs and HDAC inhibitors were reported to regulate chemokines and cytokines. Even though HDAC inhibitors have remarkable anti-tumor activity in hematological cancers, they are not effective in treating many diseases and many patients relapse after treatment. However, the role of HDACs and cytokines in regulating these diseases still remain unclear. Therefore, understanding exact mechanisms and effector functions of HDACs are urgently needed to selectively inhibit them and to establish better a platform to combat various malignancies. In this review, we address regulation of chemokines and cytokines by HDACs and HDAC inhibitors and update on HDAC inhibitors in human diseases.

Expression of the pro-inflammatory and pro-angiogenic chemokine interleukin-8 (IL-8), which is regulated at the transcriptional level by NFκB, is constitutively increased in the androgen independent metastatic prostate cancer and correlates with poor prognosis. Inhibition of NFκB-dependent transcription was used as an anti-cancer strategy for the development of the first clinically approved 26S proteasome inhibitor, bortezomib (BZ). Even though BZ has shown remarkable anti-tumor activity in hematological malignancies, it has been less effective in prostate cancer and other solid tumors; however, the mechanisms have not been fully understood. Here we report that the proteasome inhibition by BZ unexpectedly increases the IL-8 expression in androgen independent prostate cancer PC3 and DU145 cells, while expression of other NFκB-regulated genes is inhibited or unchanged. The BZ-increased IL-8 expression is associated with increased in vitro p65 NFκB DNA binding activity and p65 recruitment to the endogenous IL-8 promoter. In addition, proteasome inhibition induces a nuclear accumulation of IKKα and inhibition of IKKα enzymatic activity significantly attenuates the BZ-induced p65 recruitment to IL-8 promoter and IL-8 expression, demonstrating that the induced IL-8 expression is mediated, at least partly, by IKKα. Together, these data provide the first evidence for the gene specific increase of IL-8 expression by the proteasome inhibition in prostate cancer cells and suggest that targeting both IKKα and the proteasome may increase the BZ effectiveness in androgen independent prostate cancer treatment.

Although inhibitors of epigenetic regulators have been effective in the treatment of cutaneous T cell lymphoma (CTCL) and other hematopoietic malignancies, they have been less effective in solid tumors, including ovarian cancer (OC). We have previously shown that inhibition of histone deacetylase (HDAC) activity induces expression of the pro-inflammatory and pro-angiogenic chemokine interleukin-8 (CXCL8, IL-8) in OC cells, resulting in their increased survival and proliferation. Here, we show that in addition to ovarian cancer SKOV3, OVCAR3, and CAOV3 cells, HDAC inhibition induces the CXCL8 expression in HeLa cells, but not in CTCL Hut-78 cells. In OC cells, the CXCL8 expression is induced by pharmacological inhibition of class I HDACs. Interestingly, while an individual suppression of HDAC1, HDAC2, or HDAC3 by corresponding siRNAs inhibits the CXCL8 expression, their simultaneous suppression induces the CXCL8 expression. The induced CXCL8 expression in OC cells is dependent on histone acetyltransferase (HAT) activity of CREB-binding protein (CBP), but not p300, and is associated with HAT-dependent p65 recruitment to CXCL8 promoter. Together, our results show that the CXCL8 expression in OC cells is induced by combined inhibition of HDAC1, -2, and -3, and silenced by suppression of HAT activity of CBP. In addition, our data indicate that the induced CXCL8 expression may be responsible for the limited effectiveness of HDAC inhibitors in OC and perhaps other solid cancers characterized by CXCL8 overexpression, and suggest that targeting class I HDACs and CBP may provide novel combination strategies by limiting the induced CXCL8 expression.

Ovarian cancer is associated with increased expression of the pro-angiogenic chemokine interleukin-8 (IL-8, CXCL8), which induces tumor cell proliferation, angiogenesis, and metastasis. Even though bortezomib (BZ) has shown remarkable anti-tumor activity in hematological malignancies, it has been less effective in ovarian cancer; however, the mechanisms are not understood. We have recently shown that BZ unexpectedly induces the expression of IL-8 in ovarian cancer cells in vitro, by IκB kinase (IKK)-dependent mechanism. Here, we tested the hypothesis that IKK inhibition reduces the IL-8 production and increases BZ effectiveness in reducing ovarian tumor growth in vivo. Our results demonstrate that the combination of BZ and the IKK inhibitor Bay 117085 significantly reduces the growth of ovarian tumor xenografts in nude mice when compared to either drug alone. Mice treated with the BZ/Bay 117085 combination exhibit smallest tumors, and lowest levels of IL-8. Furthermore, the reduced tumor growth in the combination group is associated with decreased tumor levels of S536P-p65 NFκB and its decreased recruitment to IL-8 promoter in tumor tissues. These data provide the first in vivo evidence that combining BZ with IKK inhibitor is effective, and suggest that using IKK inhibitors may increase BZ effectiveness in ovarian cancer treatment.