Violacein negatively modulates the colorectal cancer survival and epithelial-mesenchymal transition.

Violacein is a secondary metabolite produced by several microorganisms including Chromobacterium violaceum, and it is already used in food and cosmetics. However, due to its potent anticancer and low side effects, its molecular action needs to be deeply scrutinized. Therefore, the main objective of this study was to evaluate the violacein's ability to interfere with three cancer hallmarks: growth factors receptor-dependent signaling, proliferation, and epithelial-mesenchymal transition (EMT). Violacein has been associated with the induction of apoptosis in colorectal cancer (CRC) cells. Here, we demonstrate that this molecule is also active in CRC spheroids and inhibits cell migration. Violacein treatment reduced the amount of EGFR and AXL receptors in the HT29 cell line. Accordingly, the inhibition of the AKT, ERK, and PKCδ kinases, which are downstream mediators of the signaling pathways triggered by EGFR and AXL, is detected. Another interesting finding was that even when the cells were stimulated with transforming growth factor-ß, the EMT marker (N-cadherin) decreased. Therefore, this study provides further evidence that reinforces the potential of violacein as an antitumor agent, once this biomolecule can "switch off" properties associated with cancer plasticity.

Platelet-dependent signaling and Low Molecular Weight Protein Tyrosine Phosphatase expression promote aggressive phenotypic changes in gastrointestinal cancer cells.

Over the last decades, some members of the protein tyrosine phosphatase family have emerged as cancer promoters. Among them, the Low Molecular Weight Protein Tyrosine Phosphatase (LMWPTP) has been described to be associated with colorectal cancer liver metastasis and poor prostate cancer prognosis. Of importance in the process of cancer progression and metastasis is the interaction between tumor cells and platelets, as the latter are thought to promote several tumor hallmarks. Here, we examine to what extent LMWPTP expression in tumor cells affects their interaction with platelets. We demonstrate that the gene encoding LMWPTP is overexpressed in upper gastrointestinal (GI) cancer cell as well as colorectal cancer, and subsequently employ cell line models to show that the level of this phosphatase may be further augmented in the presence of platelets. We demonstrate that tumor-platelet interaction promotes GI tumor cell proliferation. Additionally, using know-down/-out models we show that LMWPTP expression in cancer cells contributes to a more efficient interaction with platelets and drives platelet-induced proliferation. These data are the first to demonstrate that phosphatases play a positive role in the tumor-promoting activities of platelets, with LMWPTP emerging as a key player promoting oncogenic phenotypic changes in tumor cells.

LMWPTP modulates the antioxidant response and autophagy process in human chronic myeloid leukemia cells.

In the last decade, several reports highlight the importance of the low molecular weight protein tyrosine phosphatase (LMWPTP) in cancer aggressiveness and resistance. Specifically, in chronic myeloid leukemia, we have reported that high expression of the LMWPTP maintains Src and Bcr-Abl kinases in an activated status and the glucose metabolism is directed to lactate production and, in turn, favor the pentoses pathway (one of the key process for antioxidant and protective responses). In this present study, we investigated the possible correlation between the LMWPTP and autophagy. In resistant chronic myeloid leukemia cells, the antioxidant response is supported by the glycolytic metabolism and antioxidant enzymes such as SOD and catalase, both favored by the LMWPTP. Therefore, when the cells were challenged by hydrogen peroxide treatment, the LMWPTP level goes down as well as SOD, and in turn, autophagy process was stimulated. The findings presented here reveal a novel aspect by which LMWPTP cooperates for the resistance of CML towards stressor stimuli.