title: Rhapontigenin inhibits TGF-β-mediated epithelial‑mesenchymal transition via the PI3K/AKT/mTOR pathway and is not associated with HIF-1α degradation.
abstract: The epithelial-mesenchymal transition (EMT) is a pivotal event in cancer cell invasion and metastasis. Emerging evidence suggests that rhapontigenin (Rha) may impede the progression of cancer by disrupting angiogenesis and the EMT. However, the underlying mechanism of Rha has not yet been clarified. In this study, we used transforming growth factor β (TGF-β) to trigger EMT in diverse types of cancer cells and revealed that Rha inhibited TGF-β-induced EMT and derived‑cell invasiveness. The effects of TGF-β were blocked by Rha via interference with the PI3K/AKT/mTOR/GSK3β/β‑catenin signaling pathway. Furthermore, Rha also inhibited TGF-β‑induced expression of transcription regulators Snail and hypoxia-inducible factor 1α (HIF-1α) by causing their degradation by the 26S proteasome. Surprisingly, although HIF-1α was degraded with Snail as a result of Rha exposure, HIF-1α was not a key factor involved in TGF-β-mediated EMT induced by Rha. Knocking-down Snail expression, but not HIF-1α expression, by RNA interference dramatically reversed TGF-β-mediated EMT. Moreover, Rha abolished TGF-β-triggered cell invasiveness. Our results demonstrate that Rha inhibits TGF-β-induced EMT in cancer cells by suppressing the activity of the PI3K/AKT/mTOR pathway. Therefore, Rha may represent a new route for therapeutic intervention in cancer patients and merits future studies to assess its potential.
authors.affiliation: Department and Graduate Institute of Microbiology, College of Medicine, Taipei, Taiwan, R.O.C.
authors.forename: Yen-Hsiu
authors.initials: YH
authors.lastname: Yeh
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei City, Taiwan, R.O.C.
authors.forename: Shih-Wei
authors.initials: SW
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan, R.O.C.
authors.forename: Yen-Cheng
authors.initials: YC
authors.lastname: Yeh
authors.affiliation: Department of Emergency Medicine, Sijhih Cathay General Hospital, New Taipei City, Taiwan, R.O.C.
authors.forename: Ho-Fu
authors.initials: HF
authors.lastname: Hsiao
authors.affiliation: Department and Graduate Institute of Microbiology, College of Medicine, Taipei, Taiwan, R.O.C.
authors.forename: Tsai-Kun
authors.initials: TK
authors.lastname: Li
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D058750:Epithelial-Mesenchymal Transition; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000502:physiology*; D054875:Ubiquitination
chemical_list: D000970:Antineoplastic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019869:Phosphatidylinositol 3-Kinases; D046988:Proteasome Endopeptidase Complex; D051057:Proto-Oncogene Proteins c-akt; D000071250:Snail Family Transcription Factors; D013267:Stilbenes; D058570:TOR Serine-Threonine Kinases; D053773:Transforming Growth Factor beta1; C497442:HIF1A protein, human; C000604407:SNAI1 protein, human; C508960:TGFB1 protein, human; C431126:rhapontigenin; C546842:MTOR protein, human