PMA-induced reduction in invasiveness is associated with hyperphosphorylation of MARCKS and talin in invasive bladder cancer cells

Abstract

Protein kinase C (PKC) plays a critical role in signal transduction for a variety of cell activation processes. Enhanced PKC activity is often found in cancer cells that show marked invasive and/or metastatic potential. Thus, a specific PKC inhibitor may serve as a tool to reduce invasive or metastatic potential of cancer cells. We show here that phorbol 12‐myristate 13‐acetate (PMA), a PKC activator, also reduces invasiveness of EJ invasive transitional carcinoma cells. PMA‐induced reduction in invasiveness was parallel with inhibition of cell motility. PMA neither induced E‐cadherin expression nor augmented cell‐matrix adhesion of EJ cells. PMA caused retraction of microspikes from the rim of the cells and consequently rounding of the cellular rim, and the disappearance of microfilaments from the cytoplasm. PMA at 10−7 M, at which concentration the motility of EJ cells was completely inhibited, down‐regulated PKC activity over 5 hr after transient translocation of PKC activity to the membrane fraction. At the same time, PMA induced hyperphosphorylation of MARCKS and talin. During the process of cell movement, actin‐binding proteins are in a cycle of phosphorylation and dephosphorylation. Once this cycle is interrupted, cells can no longer maintain the dynamics of cytoskeletal structure. We suggest that retention of the hyperphosphorylated state of MARCKS and talin is responsible for the mechanism(s) by which PMA produces inhibitory activity against invasiveness of EJ cells. Int. J. Cancer 75:774–779, 1998.© 1998 Wiley‐Liss, Inc.

Robust semiparametric gene‐environment interaction analysis using sparse boosting

“…34 The copy-number loss of gene LYRM7 has been observed in at least approximately 20% of STADs, indicating its important role in STADs. 35 The retention of the hyperphosphorylated state of gene MARCKS has been shown to be responsible for certain mechanisms of protein kinase C. 36 Gastric carcinoma and adenocarcinoma cells often show dysregulated protein kinase C-dependent cell signal transduction compared to normal gastric cells, supporting MARCKS as a potential biomarker in gastric cancer. 37 It has been reported that gene PARN is upregulated in gastric tumor tissues, and PARN depletion significantly inhibits the proliferation of gastric cancer cell lines MKN28 and AGS and promotes cell death.…”

A peptide that inhibits function of Myristoylated Alanine-Rich C Kinase Substrate (MARCKS) reduces lung cancer metastasis

“…14,15 In contrast, MARCKS phosphorylation seems to inhibit bladder cancer invasiveness. 16 Inactivating mutations of MARCKS is known to be implicated with intestinal adenocarcinoma formation. 17 Interestingly, MARCKS has been reported to be not only pro-metastatic 18,19 but also a growth suppressor 20,21 in glioma and melanoma cells.…”

Apical accumulation of MARCKS in neural plate cells during neurulation in the chick embryo

“…Conversely, calcium-calmodulin binding inhibits PSD phosphorylation and actin crosslinking. In addition to neural tube closure, MARCKS and MacMARCKS have been implicated in several other events related to actin cytoskeleton, such as cell motility, cell spreading, membrane ruffling, phagocytosis, exocytosis and neurite outgrowth [13,19,20,21,22,23,24]. …”