title: Influences of lovastatin on membrane ion flow and intracellular signaling in breast cancer cells.
abstract: Lovastatin, an inhibitor of cellular cholesterol synthesis, has an apparent anti-cancer property, but the detailed mechanisms of its anti-cancer effects remain poorly understood. We investigated the molecular mechanism of Lovastatin anti-tumor function through the study of its effect on membrane ion flow, gap junctional intercellular communication (GJIC), and the pathways of related signals in MCF-7 mammary cancer cells. After treatment for 24-72 h with 4, 8 or 16 micromol/L Lovastatin, cellular proliferation was examined via the MTT assay, and changes in membrane potential and cellular [Ca(2+)](i) were monitored using confocal laser microscopy. In addition, the expression of plasma membrane calcium ATPase isoform 1 (PMCA1) mRNA was analyzed via RT-PCR, the GJIC function was examined using the scrape-loading dye transfer (SLDT) technique, and MAPK phosphorylation levels were tested with the kinase activity assay. The results showed that Lovastatin treatment significantly inhibited the growth of MCF-7 breast cancer cells. It also increased the negative value of the membrane potential, leading to the hyperpolarization of cells. Moreover, Lovastatin treatment continuously enhanced [Ca(2+)](i), although the levels of PMCA1 mRNA were unchanged. GJIC was also upregulated in MCF-7 cells, with transfer of LY Fluorescence reaching 4 to 5 rows of cells from the scraped line after treatment with 16 micromol/L Lovastatin for 72 h. Finally, downregulation of ERK1 and p38(MAPK) phosphorylation were found in Lovastatin-treated MCF-7 cells. It could be deduced that Lovastatin can induce changes in cellular hyperpolarization and intracellular Ca(2+) distributions, and increase GJIC function. These effects may result in changes in the downstream signal cascade, inhibiting the growth of MCF-7 cells.
authors.affiliation: Department of Nutrition and Food Hygiene, Third Military Medical University, Chongqing, PR China.
authors.forename: Na
authors.initials: N
authors.lastname: Wei
authors.forename: Man Tian
authors.initials: MT
authors.lastname: Mi
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D052160:Benzothiazoles / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D002232:Carbocyanines / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005453:Fluorescence; D017629:Gap Junctions / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D008148:Lovastatin / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects*; D018613:Microscopy, Confocal; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C506952:ATP2B1 protein, human; D000970:Antineoplastic Agents; D052160:Benzothiazoles; D002232:Carbocyanines; D012333:RNA, Messenger; C012944:3,3'-dipropyl-2,2'-thiadicarbocyanine; D008148:Lovastatin; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D053499:Plasma Membrane Calcium-Transporting ATPases; D002118:Calcium