2. Academic Validation
  3. RUVBL1/RUVBL2 ATPase Activity Drives PAQosome Maturation, DNA Replication and Radioresistance in Lung Cancer

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

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: john.minna@utsouthwestern.edu.
  • 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: ralf.kittler@utsouthwestern.edu.
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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