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

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.

• Authors: Paul Yenerall, Amit K Das, Shan Wang, Rahul K Kollipara, Long Shan Li, Pamela Villalobos, Josiah Flaming, Yu-Fen Lin, Kenneth Huffman, Brenda C Timmons, Collin Gilbreath, Rajni Sonavane, Lisa N Kinch, Jaime Rodriguez-Canales, Cesar Moran, Carmen Behrens, Makoto Hirasawa, Takehiko Takata, Ryo Murakami, Koichi Iwanaga, Benjamin P C Chen, Nick V Grishin, Ganesh V Raj, Ignacio I Wistuba, John D Minna, Ralf Kittler
• Journal: Cell chemical biology (Cell Chem Biol) Vol. 27 Issue 1 Pg. 105-121.e14 (01 16 2020) ISSN: 2451-9448 [Electronic] United States
• PMID: 31883965 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Carrier Proteins
• Enzyme Inhibitors
• Multiprotein Complexes
• ATPases Associated with Diverse Cellular Activities
• DNA Helicases
• RUVBL1 protein, human
• RUVBL2 protein, human

Topics

• ATPases Associated with Diverse Cellular Activities (antagonists & inhibitors, genetics, metabolism)
• Antineoplastic Agents (chemistry, pharmacology)
• Carcinoma, Non-Small-Cell Lung (diagnosis, drug therapy, metabolism)
• Carrier Proteins (antagonists & inhibitors, genetics, metabolism)
• DNA Helicases (antagonists & inhibitors, genetics, metabolism)
• DNA Replication (drug effects)
• Enzyme Inhibitors (chemistry, pharmacology)
• Humans
• Lung Neoplasms (diagnosis, drug therapy, metabolism)
• Molecular Structure
• Multiprotein Complexes (antagonists & inhibitors, genetics, metabolism)
• Radiation Tolerance