title: Demethoxycurcumin inhibits energy metabolic and oncogenic signaling pathways through AMPK activation in triple-negative breast cancer cells.
abstract: Demethoxycurcumin (DMC), curcumin (Cur), and bisdemethoxycurcumin (BDMC) are major forms of curcuminoids found in the rhizomes of turmeric. This study examined the effects of three curcuminoid analogues on breast cancer cells. The results revealed that DMC demonstrated the most potent cytotoxic effects on breast cancer MDA-MB-231 cells. Compared with estrogen receptor (ER)-positive or HER2-overexpressing breast cancer cells, DMC demonstrated the most efficient cytotoxic effects on triple-negative breast cancer (TNBC) cells. However, nonmalignant MCF-10A cells were unaffected by DMC treatment. The study showed that DMC activated AMPK in TNBC cells. Once activated, AMPK inhibited eukaryotic initiation factor 4E-binding protein-1 (4E-BP1) signaling and mRNA translation via mammalian target of rapamycin (mTOR) and decreased the activity and/or expression of lipogenic enzymes, such as fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC). DMC also targeted multiple AMPK downstream pathways. Among these, the dephosphorylation of Akt is noteworthy because it circumvents the feedback activation of Akt that results from mTOR inhibition. Moreover, DMC suppressed LPS-induced IL-6 production, thereby blocking subsequent Stat3 activation. In addition, DMC also sustained epidermal growth factor receptor (EGFR) activation by suppressing the phosphatases, PP2a and SHP-2. These results suggest that DMC is a potent AMPK activator that acts through a broad spectrum of anti-TNBC activities.
authors.affiliation: Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan.
authors.forename: Jiunn-Min
authors.initials: JM
authors.lastname: Shieh
authors.forename: Yung-Chan
authors.initials: YC
authors.lastname: Chen
authors.forename: Ying-Chao
authors.initials: YC
authors.lastname: Lin
authors.forename: Jia-Ni
authors.initials: JN
authors.lastname: Lin
authors.forename: Wei-Chih
authors.initials: WC
authors.lastname: Chen
authors.forename: Yang-Yuan
authors.initials: YY
authors.lastname: Chen
authors.forename: Chi-Tang
authors.initials: CT
authors.lastname: Ho
authors.forename: Tzong-Der
authors.initials: TD
authors.lastname: Way
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000737:chemistry / Q000378:metabolism; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D063646:Carcinogenesis / Q000187:drug effects*; D045744:Cell Line, Tumor; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology; D036381:Diarylheptanoids; D004734:Energy Metabolism / Q000187:drug effects*; D020536:Enzyme Activators / Q000494:pharmacology; D005260:Female; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control
chemical_list: D016588:Anticarcinogenic Agents; D036381:Diarylheptanoids; D020536:Enzyme Activators; D055372:AMP-Activated Protein Kinases; D003474:Curcumin; C050229:demethoxycurcumin