title: Role of STAT3/5 and Bcl-2/xL in 2-methoxyestradiol-induced endoreduplication of nasopharyngeal carcinoma cells.
abstract: 2-methoxyestradiol (2ME2), an endogenous metabolite of 17-β-estradiol, has been shown to induce apoptosis and cell cycle arrest in various tumor models. We have previously shown that 2ME2 induced endoreduplication in a well-differentiated nasopharyngeal carcinoma (NPC) HK-1 and a poorly differentiated C666-1 cell line. In the present study, we studied the survival factors involved in 2ME2-induced endoreduplicating NPC cells. In the HK-1 cells, knockdown of BcL-xL expression by siRNA resulted in the reduction of endoreduplication and an increase in the percentage of apoptosis. Further mechanistic study revealed that 2ME2 enhanced the expression of the phosphorylated form of STAT5 (p-STAT5-Y694), but not p-STAT3 (Y705) and p-STAT3 (S727), in the nucleus of HK-1 cells. Pre-treatment of cells with JAK/STAT inhibitor AG490 and STAT5 inhibitor resulted not only in the reduced expression of Bcl-xL, but also reduced the percentage of endoreduplicating cells. In contrast, 2ME2 enhanced the expression of p-STAT3 in the poorly differentiated C666-1 cells. Pharmacological inhibition of STAT3 or Bcl-2/xL resulted in a decrease in endoreduplication of C666-1 cells. Taken together, the expression of p-STAT5 and p-STAT3 was upregulated in 2ME2-induced endoreduplicating HK-1 and C666-1 cells, respectively. Combination of 2ME2 with Bcl-2/xL inhibitor is a novel strategy to reduce the formation of endoreduplicating cells during chemotherapeutic treatment of NPC. © 2011 Wiley Periodicals, Inc.
authors: Department of Biology, Hong Kong Baptist University, State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, P.R. China.
authors: C M
authors: CM
authors: Ting
authors: Chris K C
authors: CK
authors: Wong
authors: R N S
authors: RN
authors: Wong
authors: K W
authors: KW
authors: Lo
authors: Anne W M
authors: AW
authors: Lee
authors: George S W
authors: GS
authors: Tsao
authors: Maria L
authors: ML
authors: Lung
authors: N K
authors: NK
authors: Mak
mesh_terms: D000077584:2-Methoxyestradiol; D001483:Base Sequence; D015153:Blotting, Western; D002277:Carcinoma; D045744:Cell Line, Tumor; D062951:Endoreduplication / Q000187:drug effects*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor / Q000502:physiology*; D050799:STAT5 Transcription Factor / Q000502:physiology*; D051020:bcl-X Protein / Q000502:physiology*
chemical_list: C494811:BCL2L1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D051020:bcl-X Protein; D004958:Estradiol; D000077584:2-Methoxyestradiol