2-Methoxyestradiol induces mitochondria dependent apoptotic signaling in pancreatic cancer cells.
The antiproliferative action of 2-methoxyestradiol (2-ME), an endogenous estrogen metabolite is specific for cancer cells and is mediated by the induction of programmed cell death or apoptosis. But the identity of the downstream effectors of apoptotic signaling induced by 2-ME is not known. In the present study, we explored the effect of 2-ME on apoptosis in a panel of human pancreatic cancer cell lines. We have identified two categories of pancreatic cancer cell lines, which are either sensitive to 2-ME such as MIA PaCa-2, CFPAC-1, PANC-1, or non-sensitive to 2-ME such as Hs 766T. The results presented here indicated that the cell lines responsive to 2-ME could undergo apoptosis either by G2-M arrest (PANC-1) with Bcl-x(L) phosphorylation or by the accumulation of tetraploid cells in G1-S region (MIA PaCa-2) without Bcl-2/ Bcl-x(L) phosphorylation. Furthermore, 2-ME induced apoptosis in pancreatic cancer cells is mitochondria dependent as evident by the release of cytochrome c into the cytosol. 2-ME exposed cells exhibit Bid cleavage that is accompanied by the translocation of Bax into the mitochondria. Also 2-ME could induce phosphorylation of Bcl-x(L) in G2-M arrested cells, thus indicating the involvement of various anti- and pro-apoptotic regulators in the signaling cascade. The dissection of differential response of pancreatic cancer cell lines holds promise for future therapeutic intervention.
Qanungo
Suparna
S
Department of Research, Pharmacology, Ireland Cancer Center, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio, OH 44109, USA.
Basu
Aruna
A
Das
Madhusudan
M
Haldar
Subrata
S
D000077584:2-Methoxyestradiol; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D004958:Estradiol; D000077584:2-Methoxyestradiol