No abstract

E‐cadherin, a central component of the adherens junction (AJ), is a single‐pass transmembrane protein that mediates cell–cell adhesion. The loss of E‐cadherin surface expression, and therefore cell–cell adhesion, leads to increased cell migration and invasion. Treatment of colorectal cancer (CRC)‐derived cells (SW‐480 and HT‐29) with 2.0 mM metformin promoted a redistribution of cytosolic E‐cadherin to de novo formed puncta along the length of the contacting membranes of these cells. Metformin also promoted translocation from the cytosol to the plasma membrane of p120‐catenin, another core component of the AJs. Furthermore, E‐cadherin and p120‐catenin colocalized with β‐catenin at cell–cell contacts. Western blot analysis of lysates of CRC‐derived cells revealed a substantial metformin‐induced increase in the level of p120‐catenin as well as E‐cadherin phosphorylation on Ser838/840, a modification associated with β‐catenin/E‐cadherin interaction. These modifications in E‐cadherin, p120‐catenin and β‐catenin localization suggest that metformin induces rebuilding of AJs in CRC‐derived cells. Those modifications were accompanied by the inhibition of focal adhesion kinase (FAK), as revealed by a significant decrease in the phosphorylation of FAK at Tyr397 and paxillin at Tyr118. These changes were associated with a reduction in the numbers, but an increase in the size, of focal adhesions and by the inhibition of cell migration. Overall, these observations indicate that metformin targets multiple pathways associated with CRC development and progression.

Protein kinase D1 (PKD1) plays a vital role in signal transduction, cell proliferation, membrane trafficking, and cancer; however, the majority of the studies up to date had centered primarily on PKD1 functions in interphase, very little is known about its role during cell division. We previously demonstrated that during mitosis PKD1 is activated and associated with centrosomes, spindles, and midbodies. However, these observations did not address whether PKD1 was associated with mitosis regulation.Accordingly, we used rapidly acting PKD-specific inhibitors to examine the contribution of PKD1 the sequence of events in mitosis. We found that although PKD1 overexpression did not affect mitosis progression, suppression of its catalytic activity by two structurally unrelated inhibitors (kb NB 142-70 and CRT 0066101) induced a significant delay in metaphase to anaphase transition time. PKD1 inhibition during mitosis also produced the appearance of abnormal spindles, defects in chromosome alignment, and segregation as well as apoptosis. Thus, these observations indicate that PKD1 activity is associated with mitosis regulation. K E Y W O R D S cancer, mitosis, PKD1

Colorectal cancer (CRC) is one of the main causes of cancer-related mortality in the developed world despite recent developments in detection and treatment. Several epidemiological studies indicate that metformin, a widely prescribed antidiabetic drug, exerts a protective effect on different cancers including CRC. Furthermore, a recent double-blind placebo-controlled, randomized trial showed that metformin significantly decreased colorectal adenoma recurrence. Studies exploring the mechanism of action of metformin in cells derived from different types of cancers reported many effects including respiratory chain complex 1 inhibition, Akt phosphorylation inhibition, ATP depletion, PKA activation and Wnt signaling inhibition. However, many of these results were obtained employing metformin at concentrations several fold higher than those achieved in target tissues in diabetic patients receiving therapeutic recommended doses of metformin. In contrast, recent studies obtained with metformin at concentrations compatible with those detected in human intestines revealed that metformin elicit responses that target β-catenin, PI3K/Akt, E-cadherin, p120-catenin and focal adhesion kinase which are key molecules and signaling pathways associated to colorectal cancer development. This brief review revisit several know aspects as well as novel ones on the effects of metformin on cancer cells.