Hpr6.6 protein mediates cell death from oxidative damage in MCF-7 human breast cancer cells.
Reactive oxygen species (ROS) cause cell death and are associated with a variety of maladies, from trauma and infection to organ degeneration and cancer. Cells mount a complex response to oxidative damage that includes signaling from transmembrane receptors and intracellular kinases. We have analyzed the response to oxidative damage in human breast cancer cells expressing the Hpr6.6 (human membrane progesterone receptor) protein. Although Hpr6.6 is related to a putative progesterone-binding protein, Hpr6.6 is widely expressed in epithelial tissues and shares close homology with a budding yeast damage response protein called Dap1p (damage response protein related to membrane progesterone receptor). We report here that the Hpr6.6 protein regulates the response to oxidative damage in breast cancer cells. Expression of Hpr6.6 in MCF-7 cells sensitized the cells to death following long-term/low dose or short-term/high dose treatment with hydrogen peroxide. Cell death did not occur through a typical apoptotic mechanism and corresponded with hyperphosphorylation of the Akt and IkappaB proteins. However, inhibition of Akt activation and IkappaB degradation had no effect on Hpr6.6-mediated cell death, suggesting that Hpr6.6 regulates cell death through a novel oxidative damage response pathway. Our work indicates a key regulatory function for Hpr6.6 in epithelial tissues exposed to oxidative damage.
Hand
Randal A
RA
Division of Surgical Oncology, Department of Surgery, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.
Craven
Rolf J
RJ
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001426:Bacterial Proteins; D001943:Breast Neoplasms / Q000378:metabolism; D016923:Cell Death / Q000502:physiology*; D003001:Cloning, Molecular; D004768:Enterotoxins / Q000378:metabolism; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide; D051550:I-kappa B Kinase; D021962:Membrane Microdomains / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D018384:Oxidative Stress / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species; D011980:Receptors, Progesterone / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology; D000097782:NF-kappaB-Inducing Kinase
D001426:Bacterial Proteins; D004768:Enterotoxins; D006861:Hydrogen Peroxide; D051550:I-kappa B Kinase; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species; D011980:Receptors, Progesterone; D000097782:NF-kappaB-Inducing Kinase; C115296:PGRMC1 protein, human; C082174:cytolytic enterotoxin protein, Aeromonas; C496559:CHUK protein, human; C496564:Chuk protein, mouse; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse