title: Role of PKC-ERK signaling in tamoxifen-induced apoptosis and tamoxifen             resistance in human breast cancer cells.
abstract: This study was designed to investigate the role of protein kinase C (PKC) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in tamoxifen (TAM)-induced apoptosis and drug resistance in human breast cancer cells. Drug-sensitive, or estrogen receptor (ER)-positive human breast carcinoma cells (MCF-7) and the multi-drug-resistant variant (ER-negative) MCF-7/ADR cells were treated with doses of TAM for various periods of time. Cell viability and apoptosis were assessed using cell counting, DNA fragmentation and flow cytometric analysis. We found that TAM administration caused a significant increase in apoptosis of MCF-7 cells but not MCF-7/ADR cells. Western blot analysis revealed enhanced expression of PKCδ but decreased expression of PKCα in ER-positive MCF-7 cells; while ER-negative MCF-7/ADR cells had decreased levels of PKCδ and increased levels of PKCα. Interestingly, we observed that in MCF-7 cells, TAM stimulated apoptosis by promoting rapid activation of PKCδ, antagonizing downstream signaling of ERK phosphorylation; while in MCF-7/ADR cells, TAM upregulated PKCα, which promoted ERK phosphorylation. These results suggest that PKCδ enhances apoptosis in TAM-treated MCF-7 cells by antagonizing ERK phosphorylation; while the PKCα pathway plays an important role in TAM-induced drug resistance by activating ERK signaling in MCF-7/ADR cells. The combination of TAM with PKCα and ERK inhibitors could promote TAM-induced apoptosis in breast cancer cells.
authors.affiliation: Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, PR China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Li
authors.forename: Na
authors.initials: N
authors.lastname: Wang
authors.forename: Jieyu
authors.initials: J
authors.lastname: Fang
authors.forename: Jintao
authors.initials: J
authors.lastname: Huang
authors.forename: Fen
authors.initials: F
authors.lastname: Tian
authors.forename: Chaohong
authors.initials: C
authors.lastname: Li
authors.forename: Fukang
authors.initials: F
authors.lastname: Xie
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001578:Benzopyrans / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002227:Carbazoles; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D051571:Protein Kinase C-alpha / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000378:metabolism; D011960:Receptors, Estrogen / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D000098:Acetophenones; D018931:Antineoplastic Agents, Hormonal; D001578:Benzopyrans; D002227:Carbazoles; D005419:Flavonoids; D011960:Receptors, Estrogen; D013629:Tamoxifen; C081021:Go 6976; C085746:rottlerin; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one