The proteasome activator PA200 regulates tumor cell responsiveness to glutamine and resistance to ionizing radiation

Jennifer Blickwedehl, Scott Olejniczak, Ryan Cummings, Nilofar Sarvaiya, Ana Mantilla, Asher A Chanan Khan, Tej K. Pandita, Marion Schmidt, Craig B. Thompson, Naveen Bangia

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)937-944
Number of pages8
JournalMolecular Cancer Research
Volume10
Issue number7
DOIs
StatePublished - Jul 2012
Externally publishedYes

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Proteasome Endopeptidase Complex
Ionizing Radiation
Glutamine
Neoplasms
Cell Survival
Homeostasis
Growth
Ribosomal Protein S6 Kinases
Radiation Tolerance
Glutamic Acid
Food
Radiation Exposure

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

Cite this

The proteasome activator PA200 regulates tumor cell responsiveness to glutamine and resistance to ionizing radiation. / Blickwedehl, Jennifer; Olejniczak, Scott; Cummings, Ryan; Sarvaiya, Nilofar; Mantilla, Ana; Chanan Khan, Asher A; Pandita, Tej K.; Schmidt, Marion; Thompson, Craig B.; Bangia, Naveen.

In: Molecular Cancer Research, Vol. 10, No. 7, 07.2012, p. 937-944.

Research output: Contribution to journalArticle

Blickwedehl, J, Olejniczak, S, Cummings, R, Sarvaiya, N, Mantilla, A, Chanan Khan, AA, Pandita, TK, Schmidt, M, Thompson, CB & Bangia, N 2012, 'The proteasome activator PA200 regulates tumor cell responsiveness to glutamine and resistance to ionizing radiation', Molecular Cancer Research, vol. 10, no. 7, pp. 937-944. https://doi.org/10.1158/1541-7786.MCR-11-0493-T
Blickwedehl, Jennifer ; Olejniczak, Scott ; Cummings, Ryan ; Sarvaiya, Nilofar ; Mantilla, Ana ; Chanan Khan, Asher A ; Pandita, Tej K. ; Schmidt, Marion ; Thompson, Craig B. ; Bangia, Naveen. / The proteasome activator PA200 regulates tumor cell responsiveness to glutamine and resistance to ionizing radiation. In: Molecular Cancer Research. 2012 ; Vol. 10, No. 7. pp. 937-944.
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