Activation of protein kinase C modulates cell-cell and cell-substratum adhesion of a human colorectal carcinoma cell line and restores 'normal' epithelial morphology

Abnormal cell adhesion is an important contributing factor in invasion and metastasis. Here, we show that morphologically 'normal' cell-cell and cell- substratum adhesion can be restored to a poorly differentiated carcinoma ce ll line by activation of protein kinase C (PKC). This cell line, VACO IONS, grows as multicellular aggregates loosely attached to the substratum. The phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA, 7.5 nM) induces ra pid adhesive changes with 2 components. First, within 15 min of TPA the cel ls become closely apposed, an event resembling the 'compaction' seen in the mouse early embryo. Next, over 2 hr, the cells spread, forming a monolayer . We show that compaction depends on extracellular calcium, E-cadherin-medi ated adhesion and F-actin but not on protein synthesis, microtubules or sub stratum adhesion. By contrast, cell spreading is independent of cadherin an d extracellular Ca2+ but involves the formation of focal contacts containin g av integrin. TPA treatment causes rapid translocation of PKC-or to the in soluble fraction. During compaction, actin- and PKC-alpha-containing lamell ae form over the entire aggregate surface, those adjacent to the substratum appearing to initiate spreading. Compaction does not involve increased pho sphorylation of the cadherin/catenin complex. We conclude that activation o f PKC-alpha restores 'normal' morphology to these poorly differentiated cel ls. Our results are of general interest in relation to the regulation of ce ll adhesion and, through further investigation, may lead to identification of novel targets for therapeutic suppression of invasion and metastasis. (C ) 1999 Wiley-Liss, Inc.