Analysis of the proliferative response to lysophosphatidic acid in primary cultures of mammary epithelium: differences between normal and tumor cells.
The effect of lysophosphatidic acid (LPA) on the proliferation of normal and tumor mouse mammary epithelial cells in primary, serum-free, collagen gel cell culture was evaluated. LPA stimulated the growth of normal mammary epithelial cells from mature virgin mice. The growth of pregnancy-dependent tumors (PDT) was generally stimulated, although the response was attenuated in some of these tumors compared to normal cells. In contrast, the growth of 70% of ovarian-independent tumors (OIT) was inhibited by LPA; the remainder were unaffected. LPA stimulated cAMP accumulation and phosphoinositide (PI) hydrolysis in normal, PDT, and OIT. Thus, the regulation of adenylyl cyclase and PI-specific phospholipase C by LPA is similar in normal and tumor cells. Pertussis toxin (PT) partially inhibited LPA-stimulated growth in normal cells but did not affect LPA-stimulated PI hydrolysis or cAMP accumulation. Thus, PT-sensitive and -insensitive proliferative pathways are activated. PT also inhibited LPA-stimulated growth of PDT but generally had no effect on the growth of OIT. These results show that the mitogenic response to LPA is attenuated in the hormone-dependent phenotype and switches to growth inhibition in hormone-independent tumors. Furthermore, LPA stimulates multiple signal transduction pathways mediated by PT-sensitive and -insensitive G proteins. The PT-sensitive pathways are not tightly coupled to the proliferative response to LPA in tumor cells. These data suggest that alterations in G protein function may occur during tumor progression.
Imagawa
W
W
Cancer Research Laboratory, University of California, Berkeley 94720.
Bandyopadhyay
G K
GK
Nandi
S
S
D037361:Adenylate Cyclase Toxin; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen; D000242:Cyclic AMP / Q000096:biosynthesis; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005260:Female; D008246:Lysophospholipids / Q000302:isolation & purification / Q000494:pharmacology*; D008321:Mammary Glands, Animal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D037342:Pertussis Toxin; D010712:Phosphatidic Acids / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D011247:Pregnancy; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D008246:Lysophospholipids; D010712:Phosphatidic Acids; D010716:Phosphatidylinositols; D010566:Virulence Factors, Bordetella; D003094:Collagen; D000242:Cyclic AMP; D037342:Pertussis Toxin; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate