Overexpression of Multifunctional Protein p32 Promotes a Malignant Phenotype in Colorectal Cancer Cells.

p32 is a multifunctional and multicompartmental protein that has been found upregulated in numerous adenocarcinomas, including colorectal malignancy. High levels of p32 expression have been correlated with poor prognosis in colorectal cancer. However, the functions performed by p32 in colorectal cancer have not been characterized.

Signaling Pathways Involved in Nutrient Sensing Control in Cancer Stem Cells: An Overview.

Cancer cells characteristically have a high proliferation rate. Because tumor growth depends on energy-consuming anabolic processes, including biosynthesis of protein, lipid, and nucleotides, many tumor-associated conditions, including intermittent oxygen deficiency due to insufficient vascularization, oxidative stress, and nutrient deprivation, results from fast growth. To cope with these environmental stressors, cancer cells, including cancer stem cells, must adapt their metabolism to maintain cellular homeostasis.

Canonical and non-canonical Wnt signaling are simultaneously activated by Wnts in colon cancer cells.

The Wnt signaling pathway is a crucial regulator of the intestinal epithelium homeostasis and is altered in most colon cancers. While the role of aberrant canonical, β-catenin-dependent Wnt signaling has been well established in colon cancer promotion, much less is known about the role played by noncanonical, β-catenin-independent Wnt signaling in this type of cancer. This work aimed to characterize the noncanonical signal transduction pathway in colon cancer cells.

Functional Interaction of Hypoxia-Inducible Factor 2-Alpha and Autophagy Mediates Drug Resistance in Colon Cancer Cells.

Hypoxia and the accumulation of hypoxia-inducible factors (HIFs) in tumors have been associated with therapeutic resistance and with autophagy establishment. We examined the effects of stable knockdown of HIF-1α or HIF-2α expression on autophagy and drug resistance in colon cancer cells. We found that under normoxic conditions, malignant cells exhibit increased basal levels of autophagy, compared with non-malignant cells, in addition to the previously reported coexpression of HIF-1α and HIF-2α.

-GlcNAcylation Is Involved in the Regulation of Stem Cell Markers Expression in Colon Cancer Cells.

The dynamic -linked-N-acetylglucosamine posttranslational modification of nucleocytoplasmic proteins has emerged as a key regulator of diverse cellular processes including several hallmarks of cancer. However, the role played by this modification in the establishment of CSC phenotype has been poorly studied so far and remains unclear. In this study we confirmed the previous reports showing that colon cancer cells exhibit higher -GlcNAc basal levels than non-malignant cells, and investigated the role played by -GlcNAcylation in the regulation of CSC phenotype.

Dishevelled stability is positively regulated by PKCζ-mediated phosphorylation induced by Wnt agonists.

Dishevelled (Dvl) proteins are central mediators of both canonical and non-canonical Wnt signaling. It is well known that, upon Wnt stimulation, Dvl becomes phosphorylated. However, how Wnt-induced phosphorylation of Dvl is regulated and its consequences are poorly understood.

Data on chemical activation of Wnt/β-catenin during axolotl limb regeneration.

Limb amputation in axolotls was performed to obtain data demonstrating that a chemical agonist of Wnt (int-related protein)/β-catenin signalling can have a role in axolotl limb regeneration (Wischin et al., 2017) [1]. The data revealed that active β-catenin protein was present during limb regeneration in some Leydig cells in the epithelium; after the chemical treatment, it was observed in more Leydig cells.

Chemical activation of Wnt/β-catenin signalling inhibits innervation and causes skeletal tissue malformations during axolotl limb regeneration.

Limb regeneration involves several interrelated physiological processes in which a particular signalling pathway may play a variety of functions. Blocking the function of Wnt/β-catenin signalling during limb regeneration inhibits regeneration in axolotls (Ambystoma mexicanum). Limb development shares many features with limb regeneration, and Wnt/β-catenin activation has different effects depending on the developmental stage.

Glycogen Synthase Kinase 3β Is Positively Regulated by Protein Kinase Cζ-Mediated Phosphorylation Induced by Wnt Agonists.

The molecular events that drive Wnt-induced regulation of glycogen synthase kinase 3β (GSK-3β) activity are poorly defined. In this study, we found that protein kinase Cζ (PKCζ) and GSK-3β interact mainly in colon cancer cells. Wnt stimulation induced a rapid GSK-3β redistribution from the cytoplasm to the nuclei in malignant cells and a transient PKC-mediated phosphorylation of GSK-3β at a different site from serine 9.

Hypoxia-inducible factors modulate the stemness and malignancy of colon cancer cells by playing opposite roles in canonical Wnt signaling.

This study examined the role played by hypoxia-inducible factors (HIFs) in malignant phenotype maintenance and canonical Wnt signaling. Under normoxia, we determined that both HIF-1α and HIF-2α are expressed in human colon cancer cells but not in their non-malignant counterparts. The stable knockdown of HIF-1α or HIF-2α expression induced negative effects on the malignant phenotype of colon cancer cells, with lactate production, the rate of apoptosis, migration, CXCR4-mediated chemotaxis, and tumorigenic activity all being significantly affected by HIF knockdown and with HIF-1α depletion exerting greater effects.

Protein phosphatase 2A is essential to maintain active Wnt signaling and its Aβ tumor suppressor subunit is not expressed in colon cancer cells.

Canonical Wnt signaling is altered in most cases of colorectal cancer. Experimental evidence indicates that protein phosphatase 2A (PP2A) may play either positive or negative roles in Wnt signaling but its precise in vivo functions remain elusive. In this work, using colon cultured cell lines we showed that basal PP2A activity is markedly reduced in malignant cells compared to non-malignant counterparts.

Protein kinase C delta negatively modulates canonical Wnt pathway and cell proliferation in colon tumor cell lines.

The tumor suppressor Adenomatous Polyposis coli (APC) gene is mutated or lost in most colon cancers. Alterations in Protein kinase C (PKC) isozyme expression and aberrant regulation also comprise early events in intestinal carcinomas. Here we show that PKCδ expression levels are decreased in colon tumor cell lines with respect to non-malignant cells.

Protein kinase C in Wnt signaling: implications in cancer initiation and progression.

Although it is well known that Wnt and protein kinase C (PKC) signaling pathways are both involved in carcinogenesis and tumor progression, their synergistic contribution to these processes or the crosstalk between them has just recently been approached. The Wnt and PKC signaling are involved in many cellular functions including proliferation, differentiation, survival, apoptosis, cytoskeletal remodeling, and cell motility. Canonical Wnt signaling has been well characterized as one of the most important contributors to tumorigenesis, and it has been implicated in many types of solid tumors.

Protein kinase C ζ is a positive modulator of canonical Wnt signaling pathway in tumoral colon cell lines.

The colonic epithelium is a continuously renewing tissue with a dynamic turnover of cells. Wnt pathway is a key regulator of its homeostasis and is altered in a large proportion of colon cancers. Protein kinase C (PKC) family of serine/threonine kinases are also involved in colon tumor formation and progression; however, the molecular role played by them in the Wnt pathway, is poorly understood.

Protein kinase C is involved in the regulation of several calreticulin posttranslational modifications.

Calreticulin (CRT) is a highly versatile lectin-like chaperone that affects many cellular functions both inside and outside the endoplasmic reticulum lumen. We previously reported that calreticulin interacts with several protein kinase C isozymes both in vitro and in vivo. The aim of this study was to elucidate the molecular determinants involved in the association between these proteins and the biochemical significance of their interaction.

Posttranslational modifications on protein kinase c isozymes. Effects of epinephrine and phorbol esters.

The posttranslational modifications induced on PKC isozymes as result of their activation were investigated. Reciprocal immunoprecipitations followed by Western blot analysis demonstrated that all PKC isozymes expressed in rat hepatocytes are modified by tyrosine nitration and tyrosine phosphorylation in different ways upon exposure of cells to a direct PKC activator (TPA), or to an extracellular ligand known to activate PKC-dependent pathways (epinephrine). Our data demonstrate for the first time that all PKC isozymes are also dynamically modified by O-linked beta-N-acetylglucosamine (O-GlcNAc); the presence of this modification was confirmed in part by FT-ICR mass spectrometry analysis.