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Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS- and autophagy-dependent tumorigenic growth, but the role of KRAS in supporting autophagy has not been established. We show that, to our surprise, suppression of KRAS increased autophagic flux, as did pharmacological inhibition of its effector ERK MAPK. Furthermore, we demonstrate that either KRAS suppression or ERK inhibition decreased both glycolytic and mitochondrial functions. We speculated that ERK inhibition might thus enhance PDAC dependence on autophagy, in part by impairing other KRAS- or ERK-driven metabolic processes. Accordingly, we found that the autophagy inhibitor chloroquine and genetic or pharmacologic inhibition of specific autophagy regulators synergistically enhanced the ability of ERK inhibitors to mediate antitumor activity in KRAS-driven PDAC. We conclude that combinations of pharmacologic inhibitors that concurrently block both ERK MAPK and autophagic processes that are upregulated in response to ERK inhibition may be effective treatments for PDAC.

Purpose: MUC1 , an oncogene overexpressed in multiple solid tumors, including pancreatic cancer, reduces overall survival and imparts resistance to radiation and chemotherapies. We previously identified that MUC1 facilitates growth-promoting metabolic alterations in pancreatic cancer cells. The present study investigates the role of MUC1-mediated metabolism in radiation resistance of pancreatic cancer by utilizing cell lines and in vivo models. Experimental Design: We used MUC1 -knockdown and -overexpressed cell line models for evaluating the role of MUC1-mediated metabolism in radiation resistance through in vitro cytotoxicity, clonogenicity, DNA damage response, and metabolomic evaluations. We also investigated whether inhibition of glycolysis could revert MUC1-mediated metabolic alterations and radiation resistance by using in vitro and in vivo models. Result s: MUC1 expression diminished radiation-induced cytotoxicity and DNA damage in pancreatic cancer cells by enhancing glycolysis, pentose phosphate pathway, and nucleotide biosynthesis. Such metabolic reprogramming resulted in high nucleotide pools and radiation resistance in in vitro models. Pretreatment with the glycolysis inhibitor 3-bromopyruvate abrogated MUC1-mediated radiation resistance both in vitro and in vivo , by reducing glucose flux into nucleotide biosynthetic pathways and enhancing DNA damage, which could again be reversed by pretreatment with nucleoside pools. Conclusions: MUC1-mediated nucleotide metabolism plays a key role in facilitating radiation resistance in pancreatic cancer and targeted effectively through glycolytic inhibition. Clin Cancer Res; 23(19); 5881-91. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Poor response to cancer therapy due to resistance remains a clinical challenge. The present study establishes a widely prevalent mechanism of resistance to gemcitabine in pancreatic cancer, whereby increased glycolytic flux leads to glucose addiction in cancer cells and a corresponding increase in pyrimidine biosynthesis to enhance the intrinsic levels of deoxycytidine triphosphate (dCTP). Increased levels of dCTP diminish the effective levels of gemcitabine through molecular competition. We also demonstrate that MUC1-regulated stabilization of hypoxia inducible factor-1α (HIF-1α) mediates such metabolic reprogramming. Targeting HIF-1α or de novo pyrimidine biosynthesis, in combination with gemcitabine, strongly diminishes tumor burden. Finally, reduced expression of TKT and CTPS, which regulate flux into pyrimidine biosynthesis, correlates with better prognosis in pancreatic cancer patients on fluoropyrimidine analogs., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that belongs to the basic-helix-loop-helix (bHLH)-Per-ARNT-Sim (PAS) superfamily of transcription factors, mediates toxic response induced by environmental chemicals such as polycyclic aromatic hydrocarbons (PAH). AhR is expressed at high levels in several human breast carcinoma cell lines in direct correlation with the degree of their malignancy. Recent studies suggest a possible role for AhR in cancer independent of PAH. Therefore, we established stable AhR knockdown cells of the human breast cancer cell line MDA-MB-231 and analyzed their tumorigenic properties in in vitro and in vivo model systems. In addition we analyzed their response to radiation and chemotherapeutic treatment. AhR knockdown attenuated these cells tumorigenic properties in vitro including proliferation, anchorage independent growth, migration and apoptosis and reduced orthotopic xenograft tumor growth and lung metastasis in vivo. Notably, we observed that AhR knockdown enhanced radiation-induced apoptosis as well as significantly decreased cell clonogenic survival. Furthermore, AhR knockdown in MDA-MB-231 cells sensitized them to paclitaxel treatment, evident by a decrease in the required cytotoxic dose. Subsequent analysis revealed AhR knockdown significantly reduced phosphorylation of AKT, which impacts cell proliferation and survival. Apoptosis-focused gene expression analyses revealed an altered expression of genes regulating apoptosis in MDA-MB-231 cells. Collectively, our data identify AhR as a potential novel therapeutic target in the treatment of metastatic breast cancer., (Copyright © 2013 UICC.)

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates a battery of genes in response to exposure to a broad class of environmental poly aromatic hydrocarbons (PAH). AhR is historically characterized for its role in mediating the toxicity and adaptive responses to these chemicals, however mounting evidence has established a role for it in ligand-independent physiological processes and pathological conditions, including cancer. The AhR is overexpressed and constitutively activated in advanced breast cancer cases and was shown to drive the progression of breast cancer. In this article we will review the current state of knowledge on the possible role of AhR in breast cancer and how it will be exploited in targeting AhR for breast cancer therapy.

Protein Kinase C (PKC) exists as one of twelve serine/threonine isoforms and has been found to mediate ethanol-induced activation of the Mitogen-Activated Protein Kinase (MAPK) pathway. The aim of this study was to determine the PKC isoform(s) that are mediators of ethanol-induced MAPK activity (ERK 1 and 2) and to verify the necessity of calcium in this activation process using cell culture in the presence and absence of ethanol, and other agents that modulate PKC expression. Western blotting analysis was used to assess the effect of ethanol on activating classical (alpha/ssII), novel (delta) and atypical (zeta/lambda) PKC isoforms in vascular smooth muscle cells (VSMCs). The results indicate that ethanol treated VSMCs express the classical PKC-alpha/ssII, novel PKC-delta, and atypical PKC-zeta/lambda isoforms. The expression of PKC-alpha/ssII was inhibited within the first two min of stimulation, followed by activation with maximum expression at 10 min. Similarly, PKC-delta and zeta expressions were suppressed during the first two min of ethanol stimulation with maximum increase in expressions at 10 min. The PKC inhibitor GF109203X and the calcium chelating agent BAPTA, enhanced ethanol-induced PKC expression, whereas, diltiazem reduced expression of PKC by 10% of control. On the other hand, BAPTA in the presence of GF10203X inhibited expression of ERK 1 & 2 downstream from the PKC pathway, whereas, BAPTA alone enhanced expression. These results demonstrate also that classical, novel, and atypical PKCs respond to ethanol during the initial phase of activation of ERK 1 & 2.