© 1993 by Oxford University Press
Journal of the National Cancer Institute, Vol. 85, No. 5, 402-407,
March 3, 1993
© 1993 Oxford University Press
Protein Kinase C: A Novel Target for Inhibiting Gastric Cancer Cell Invasion
Laboratory of Mammalian Cell Transformation, Memorial Sloan-Kettering Cancer Center New York, N.Y.
Sphinx Pharmaceuticals Corporation Durham, N.C.
Gastrointestinal Oncology Section, Division of Solid Tumor Oncology, Department of Medicine Memorial Sloan-Kettering Cancer Center New York, N.Y.
Correspondence to: Gary. K. Schwartz, M.D., Memorial Sloan-Kettering Cancer Center, Box 128, 1275 York Ave., New York, NY 10021.
Background: Gastric adenocarcinoma is a common neoplasm worldwide. Patients with completely resected disease often have locoregional recurrence, and adjuvant chemotherapy has failed to reduce the common occurrence of metastases. Protein kinase C (PKC) is thought to be important in tumor cell invasion, but its relationship to gastric cancer cell invasion, and thus metastases, remains unexplored. We recently identified and established invasive and noninvasive human gastric adenocarcinoma cell lines, which can now be used to test agents for inhibition of tumor cell invasion by inhibition of PKC activity. Purpose: The objectives were (a) to test threo-dihydro-sphingosine (SPC100221), a specific inhibitor of PKC at its regulatory site, and staurosporine, a potent but nonspecific inhibitor of PKC at its catalytic site, for their effects on gastric cancer cell invasion in vitro and (b) to determine whether the expression of PKC isoforms can distinguish invasive from noninvasive gastric cancer cells. Methods: Gastric cancer cell invasion through Matrigel-coated Nuclepore filters in the Boyden chamber assay was analyzed in the presence of graded concentrations of SPC100221 and staurosporine. The invasive SK-GT-1 and SK-GT-5 cell lines and the noninvasive SK-GT-2 and SK-GT-4 cell lines were used. PKC isoform expression was determined by reverse transcription of messenger RNAs to complementary DNA and subsequent amplification by the polymerase chain reaction. Results: The effects of staurosporine and SPC100221 on tumor cell invasion were tested at drug concentrations that did not inhibit cell proliferation, as evidenced by [3H]thymidine uptake. Staurosporine and SPC100221 at subtoxic doses inhibited human gastric cancer cell invasion by 50% at 5 x 10–9 M and 2 x 10–7 M, respectively. The expression of PKC
was observed in the invasive but not the noninvasive gastric cancer cells. Both types of cells, however, expressed the PKC
and PKC
isoforms. Conclusions: Gastric cancer cell invasion can be inhibited by PKC inhibitors, and expression of PKC may be a marker of invasiveness in gastric cancer. Implications: PKC appears to represent a new target for inhibition of gastric cancer cell invasion, and SPC100221, in view of its PKC specificity, may provide a model for future drug development in this area. Moreover, PKC may have a fundamental role in the development of invasive potential in gastric cancer. [J Natl Cancer Inst 85: 402–407, 1993]
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