title: Baicalein upregulates DDIT4 expression which mediates mTOR inhibition and growth inhibition in cancer cells.
abstract: Baicalein is a natural flavone that exhibits anticancer properties. Using microarrays we found that DDIT4 was the highest transcript induced by baicalein in cancer cells. We confirmed in multiple cancer cell lines large, dose-related expression of DDIT4 by quantitative RT-PCR and immunoblot, which correlates with growth inhibition. Time course experiments demonstrate that DDIT4 is rapidly inducible, with high expression maintained for several days in vitro. Induction of DDIT4 expression is p53 independent based on evaluation of p53 knockout cells. Since DDIT4 is known to inhibit mTORC1 activity we confirmed that baicalein suppresses phosphorylation of mTORC1 targets. Using RNA interference we demonstrate that mTORC1 activity and growth inhibition by baicalein is attenuated by knockdown of DDIT4. We furthermore demonstrate suppression of established tumors by baicalein in a mouse model of breast cancer with increased DDIT4 expression in the tumors. Finally, we demonstrate that baicalein upregulates DDIT4 and causes mTORC1 and growth inhibition in platinum resistant cancer cells in marked contrast to platinum chemotherapy treatment. These studies demonstrate that baicalein inhibits mTORC1 through DDIT4 expression, and may be useful in cancer chemotherapy and chemoprevention.
authors.affiliation: Departments of Surgery, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Departments of Surgery, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
authors.forename: Ernest
authors.initials: E
authors.lastname: Han
authors.affiliation: Departments of Surgery, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
authors.forename: Quanhua
authors.initials: Q
authors.lastname: Xing
authors.affiliation: Departments of Surgery, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Yan
authors.affiliation: Departments of Surgery, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Arrington
authors.affiliation: Molecular & Cellular Biology, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Wang
authors.affiliation: Departments of Surgery, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
authors.forename: Dylan
authors.initials: D
authors.lastname: Tully
authors.affiliation: Molecular & Cellular Biology, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA; Medical Oncology, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Kowolik
authors.affiliation: Molecular Medicine, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Lu
authors.affiliation: Biostatistics, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Frankel
authors.affiliation: Pathology, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhai
authors.affiliation: Departments of Surgery, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wen
authors.affiliation: Molecular Medicine, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
authors.forename: David
authors.initials: D
authors.lastname: Horne
authors.affiliation: Molecular Medicine, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
authors.forename: M L Richard
authors.initials: MLR
authors.lastname: Yip
authors.affiliation: Departments of Surgery, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA. Electronic address: jyim@coh.org.
authors.forename: John H
authors.initials: JH
authors.lastname: Yim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D044950:Flavanones / Q000008:administration & dosage / Q000494:pharmacology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; C469991:DDIT4 protein, human; D044950:Flavanones; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C006680:baicalein; D058570:TOR Serine-Threonine Kinases
keywords: Baicalein; Cellular stress; DDIT4; IRF1; mTOR