Cell growth inhibition by all-trans retinoic acid in SKBR-3 breast cancer cells: involvement of protein kinase Calpha and extracellular signal-regulated kinase mitogen-activated protein kinase.
All-trans retinoic acid (ATRA), a synthetic derivative of vitamin A, inhibits the growth of breast cancer cells. To elucidate the mechanism by which ATRA causes cell growth inhibition, we examined changes in cell cycle and intracellular signaling pathways, focusing on protein kinase C (PKC) and mitogen-activated protein kinase (MAPK). Using the estrogen receptor-negative, retinoid receptor-positive breast cancer cell line SKRB-3, we found that treatment with ATRA significantly decreased the expression of PKCalpha, as well as reducing ERK MAPK phosphorylation. ATRA treatment leads to dephosphorylation of Rb, and consequently to G(1) arrest. Marked changes in the expression of cyclins (particularly cyclins A and E) were observed in SKBR-3 cells treated with ATRA. Using a series of pharmacological and molecular approaches, we found evidence that ATRA-induced SKBR-3 cell growth inhibition involves the deregulation of the PKCalpha-MAPK pathway. These data suggest that retinoids interfered with signal transduction pathways that are crucial for cell cycle progression, and highlight the complexities of the biological effects of retinoid derivatives.
Nakagawa
Shino
S
Department of Surgery, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
Fujii
Teruhiko
T
Yokoyama
Goro
G
Kazanietz
Marcelo G
MG
Yamana
Hideaki
H
Shirouzu
Kazuo
K
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism*; D051571:Protein Kinase C-alpha; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D018168:Receptors, Retinoic Acid; D014212:Tretinoin; C496628:PRKCA protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D020928:Mitogen-Activated Protein Kinases