title: The proteasome activator PA200 regulates tumor cell responsiveness to glutamine and resistance to ionizing radiation.
abstract: The cellular response to ionizing radiation (IR) involves a variety of mechanisms to repair damage and maintain cell survival. We previously reported that the proteasome activator PA200 promotes long-term cell survival after IR exposure. The molecular function of PA200 is to enhance proteasome-mediated cleavage after glutamate; however, it is not known how this molecular function promotes survival after IR exposure. Here, we report that upon IR exposure, cellular demand for exogenous glutamine is increased. Cells containing PA200 are capable of surviving this IR-induced glutamine demand, whereas PA200-deficient cells show impaired long-term survival. Additional glutamine supplementation reverses the radiosensitivity of PA200-knockdown cells suggesting impaired glutamine homeostasis in these cells. Indeed, PA200-knockdown cells are unable to maintain intracellular glutamine levels. Furthermore, when extracellular glutamine is limiting, cells that contain PA200 respond by slowing growth, but PA200-knockdown cells and cells in which post-glutamyl proteasome activity is inhibited are nonresponsive and continue rapid growth. This cellular unresponsiveness to nutrient depletion is also reflected at the level of the mTOR substrate ribosomal S6 kinase (S6K). Thus, inability to restrict growth causes PA200-deficient cells to continue growing and eventually die due to lack of available glutamine. Together, these data indicate an important role for PA200 and post-glutamyl proteasome activity in maintaining glutamine homeostasis, which appears to be especially important for long-term survival of tumor cells after radiation exposure.
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Blickwedehl
authors.forename: Scott
authors.initials: S
authors.lastname: Olejniczak
authors.forename: Ryan
authors.initials: R
authors.lastname: Cummings
authors.forename: Nilofar
authors.initials: N
authors.lastname: Sarvaiya
authors.forename: Ana
authors.initials: A
authors.lastname: Mantilla
authors.forename: Asher
authors.initials: A
authors.lastname: Chanan-Khan
authors.forename: Tej K
authors.initials: TK
authors.lastname: Pandita
authors.forename: Marion
authors.initials: M
authors.lastname: Schmidt
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
authors.forename: Naveen
authors.initials: N
authors.lastname: Bangia
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D055785:Gene Knockdown Techniques; D005973:Glutamine / Q000378:metabolism* / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D008546:Melanoma, Experimental; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011836:Radiation Tolerance / Q000187:drug effects / Q000235:genetics; D011839:Radiation, Ionizing; D015398:Signal Transduction
chemical_list: D005973:Glutamine; D009687:Nuclear Proteins; C521188:PSME4 protein, human