The survival rate of cancer patients is steadily increasing, owing to more efficient therapies. Understanding the molecular mechanisms of chemotherapy-induced premature ovarian insufficiency (POI) could identify targets for prevention of POI. Loss of the primordial follicle reserve is the most important cause of POI, with the p53 family member p63 being responsible for DNA-damage-induced apoptosis of resting oocytes. Here, we provide the first detailed mechanistic insight into the activation of p63, a process that requires phosphorylation by both the priming kinase CHK2 and the executioner kinase CK1 in mouse primordial follicles. We further describe the structural changes induced by phosphorylation that enable p63 to adopt its active tetrameric conformation and demonstrate that previously discussed phosphorylation by c-Abl is not involved in this process. Inhibition of CK1 rescues primary oocytes from doxorubicin and cisplatin-induced apoptosis, thus uncovering a new target for the development of fertoprotective therapies.

Glutamate has been implicated in tumorigenesis through activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPAR). However, the function of a glutamate-to-AMPAR signal in pancreatic ductal adenocarcinoma (PDAC) has remained elusive. We now show that glutamate-mediated AMPA receptor activation increases invasion and migration of pancreatic cancer cells via activation of the classical MAPK pathway. Glutamate levels were increased in pancreatic cancer accompanied by downregulation of GluR subunits 1, 2, and 4. In pancreatic cancer precursor lesions, pancreatic intraepithelial neoplasia (PanIN), GluR1 subunit levels were strikingly and step-wise increased but its expression was rare in PDAC. Pharmacological inhibition or RNAi-mediated suppression of GluR1 or GluR2 did not affect cancer cell growth but significantly decreased invasion. In a K-ras wildtype cell line, AMPA receptor activation enhanced K-ras activity and-further downstream-phosphorylation of p38 and of p44/42. Preemptive blockade of AMPA receptors in a mouse model of pancreatic cancer inhibited tumor cell settling. AMPA receptor activation thus not only activates MAPK signalling but also directly increases activity of K-ras. Glutamate might serve as a molecular switch that decreases the threshold of K-ras-induced oncogenic signalling and increases the chance of malignant transformation of pancreatic cancer precursor lesions.Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human malignancies, with exceptionally low survival rates (5-year survival rate less than 5%). 1 Although the cell of origin of PDAC is controversially discussed, 2 pancreatic intraepithelial neoplasias (PanIN) of different grades (1A, 1B, 2, 3) in which increasing numbers of molecular alterations are found (i.e., mutations in the Kras, Smad4 and p53 genes), are believed to belong to the multistep progression model of pancreatic cancer. 3,4 Neurotransmitters and neuropeptides have been shown to play a role in pancreatic carcinogenesis 5-11 and in pancreas-associated diseases 8,[12][13][14][15][16] however, the role of excitatory neurotransmitters and particularly of glutamate in pancreatic cancer is not well defined. Glutamate activates metabotropic receptors (mGluR; G protein-coupled receptors) and the ionotropic (iGluR) receptors N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate 17,18 receptors. AMPA receptors are heteromeric and are assembled from the four subunits GluR1-4 in different combinations. The presence of GluR2 subunit determines AMPA receptor impermeability to Ca 2þ . 17,19,20 Since AMPA receptor activation regulates differentiation, proliferation and migration of embryonic stem cells, [21][22][23][24] it has been hypothesized that modulation of AMPA receptor-mediated signals might be involved in carcinogenesis, particularly because it has also been shown that AMPA signals via the MAPK pathway. [25][26][27] This hypothesis has subsequently been proven for some ...

Decreased ATG16L1 stabilization is associated with increased susceptibility to develop inflammatory bowel diseases. Diamanti et al. identify IKKα as a central upstream kinase of ATG16L1, providing evidence that ATG16L1 stabilization is controlled by phosphorylation downstream of TNF and NOD activation.

In colorectal cancer patients, a high density of cytotoxic CD8 T cells in tumors is associated with better prognosis. Using a Stat3 loss-of-function approach in two wnt/β-catenin-dependent autochthonous models of sporadic intestinal tumorigenesis, we unravel a complex intracellular process in intestinal epithelial cells (IECs) that controls the induction of a CD8 T cell based adaptive immune response. Elevated mitophagy in IECs causes iron(II)-accumulation in epithelial lysosomes, in turn, triggering lysosomal membrane permeabilization. Subsequent release of proteases into the cytoplasm augments MHC class I presentation and activation of CD8 T cells via cross-dressing of dendritic cells. Thus, our findings highlight a so-far-unrecognized link between mitochondrial function, lysosomal integrity, and MHC class I presentation in IECs and suggest that therapies triggering mitophagy or inducing LMP in IECs may prove successful in shifting the balance toward anti-tumor immunity in colorectal cancer.

We propose ALCAM as a novel serum biomarker in human pancreatic tumors which is associated with cell adhesion, growth and chemoresistance.