Anticancer activity of pristimerin in epidermal growth factor receptor 2-positive SKBR3 human breast cancer cells.
Pristimerin is a naturally occurring triterpenoid that causes cytotoxicity in several cancer cell lines. However, the mechanism of action for the cytotoxic effect of pristimerin has not been unexplored. The purpose of this study was to investigate the effect of pristimerin on cytotoxicity using the epidermal growth factor receptor 2 (HER2)-positive SKBR3 human breast cancer cell line. Pristimerin inhibited proliferation in dose- and time-dependent manners in cells. We found it to be effective for suppressing HER2 protein and mRNA expression. Fatty acid synthase (FASN) expression and FASN activity were downregulated by pristimerin. Adding of exogenous palmitate, the end product of de novo fatty acid synthesis, reduced the proliferation activity of pristimerin. The changes in HER2 and FASN expression induced by pristimerin altered the levels of Akt and mitogen-activated protein kinase (MAPK) phosphorylation (Erk1/2, p38, and c-Jun N-terminal kinase (JNK)). Pristimerin lowered the levels of phosphorylated mammalian target of rapamycin (mTOR) and its downstream targets such as phosphoprotein 70 ribosomal protein S6 kinase and 4E binding protein1. Pristimerin inhibited migration and invasion of cells, and co-treatment with the mTOR inhibitor rapamycin additionally suppressed these activities. Pristimerin-induced apoptosis was evaluated using Western blotting for caspase-3, -8, -9, and poly (ADP-ribose) polymerase expression and flow cytometric analysis for propidium iodide labeling. These results suggest that pristimerin is a novel HER2-downregulated compound that is able to decrease fatty acid synthase and modulate the Akt, MAPK, and mTOR signaling pathways to influence metastasis and apoptosis. Pristimerin may be further evaluated as a chemotherapeutic agent for HER2-positive breast cancers.
Department of Surgery, Chungnam National University Hospital, Daejeon 301–721, Korea.
Jin Sun
JS
Lee
In Sang
IS
Yoon
Myung Sun
MS
Lee
Eun Young
EY
Cha
Phuong Thien
PT
Thuong
Trinh Thi
TT
Diep
Je Ryong
JR
Kim
D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D054890:Fatty Acid Synthase, Type I / Q000037:antagonists & inhibitors; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D010936:Plant Extracts; D018517:Plant Roots; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D049918:Salacia; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014315:Triterpenes / Q000302:isolation & purification / Q000494:pharmacology*; D014945:Wound Healing
D000972:Antineoplastic Agents, Phytogenic; D020169:Caspases; D054890:Fatty Acid Synthase, Type I; D020928:Mitogen-Activated Protein Kinases; D053978:Pentacyclic Triterpenes; D010936:Plant Extracts; D011065:Poly(ADP-ribose) Polymerases; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; D014315:Triterpenes; C518729:FASN protein, human; C546842:MTOR protein, human; C508053:ERBB2 protein, human; C050414:celastrol