RUVBL1/RUVBL2 ATPase Activity Drives PAQosome Maturation, DNA Replication and Radioresistance in Lung Cancer

  • Cell Chem Biol. 2020 Jan 16;27(1):105-121.e14. doi: 10.1016/j.chembiol.2019.12.005.
Paul Yenerall  1 ,  Amit K Das  2 ,  Shan Wang  3 ,  Rahul K Kollipara  4 ,  Long Shan Li  2 ,  Pamela Villalobos  5 ,  Josiah Flaming  2 ,  Yu-Fen Lin  6 ,  Kenneth Huffman  2 ,  Brenda C Timmons  2 ,  Collin Gilbreath  7 ,  Rajni Sonavane  7 ,  Lisa N Kinch  8 ,  Jaime Rodriguez-Canales  5 ,  Cesar Moran  9 ,  Carmen Behrens  10 ,  Makoto Hirasawa  11 ,  Takehiko Takata  12 ,  Ryo Murakami  13 ,  Koichi Iwanaga  12 ,  Benjamin P C Chen  6 ,  Nick V Grishin  8 ,  Ganesh V Raj  14 ,  Ignacio I Wistuba  15 ,  John D Minna  16 ,  Ralf Kittler  17
Affiliations
  • 1. Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • 2. Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • 3. Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Urology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • 4. Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • 5. Department of Translational Molecular Pathology, UT M.D. Anderson Cancer Center, Houston, TX 77030, USA.
  • 6. Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • 7. Department of Urology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • 8. Howard Hughes Medical Institute and Departments of Biophysics and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 9. Department of Pathology, UT M.D. Anderson Cancer Center, Houston, TX 77030, USA.
  • 10. Department of Thoracic/Head and Neck Medical Oncology, UT M.D. Anderson Cancer Center, Houston, TX 77030, USA.
  • 11. Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi-Sankyo Co., Ltd., Tokyo 103-8426, Japan.
  • 12. Oncology Medical Science Department, Medical Affairs, Daiichi-Sankyo Co., Ltd., Tokyo 103-8426, Japan.
  • 13. Oncology Research Laboratories II, Daiichi-Sankyo Co., Ltd., Tokyo 103-8426, Japan.
  • 14. Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Urology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • 15. Department of Translational Molecular Pathology, UT M.D. Anderson Cancer Center, Houston, TX 77030, USA; Department of Thoracic/Head and Neck Medical Oncology, UT M.D. Anderson Cancer Center, Houston, TX 77030, USA.
  • 16. Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: [email protected].
  • 17. Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: [email protected].
PMID: 31883965 DOI: 10.1016/j.chembiol.2019.12.005
Abstract

RUVBL1 and RUVBL2 (collectively RUVBL1/2) are essential AAA+ ATPases that function as co-chaperones and have been implicated in Cancer. Here we investigated the molecular and phenotypic role of RUVBL1/2 ATPase activity in non-small cell lung Cancer (NSCLC). We find that RUVBL1/2 are overexpressed in NSCLC patient tumors, with high expression associated with poor survival. Utilizing a specific inhibitor of RUVBL1/2 ATPase activity, we show that RUVBL1/2 ATPase activity is necessary for the maturation or dissociation of the PAQosome, a large RUVBL1/2-dependent multiprotein complex. We also show that RUVBL1/2 have roles in DNA replication, as inhibition of its ATPase activity can cause S-phase arrest, which culminates in Cancer cell death via replication catastrophe. While in vivo pharmacological inhibition of RUVBL1/2 results in modest antitumor activity, it synergizes with radiation in NSCLC, but not normal cells, an attractive property for future preclinical development.

Keywords
DNA replication; RUVBL1; RUVBL2; non-small cell lung cancer; radiation therapy.
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