Cell Reports (Feb 2023)
Elevated PAF1-RAD52 axis confers chemoresistance to human cancers
- Sanchita Rauth,
- Koelina Ganguly,
- Pranita Atri,
- Seema Parte,
- Rama Krishna Nimmakayala,
- Venkatesh Varadharaj,
- Palanisamy Nallasamy,
- Raghupathy Vengoji,
- Ayoola O. Ogunleye,
- Imayavaramban Lakshmanan,
- Ramakanth Chirravuri,
- Mika Bessho,
- Jesse L. Cox,
- Jason M. Foster,
- Geoffrey A. Talmon,
- Tadayoshi Bessho,
- Apar Kishor Ganti,
- Surinder K. Batra,
- Moorthy P. Ponnusamy
Affiliations
- Sanchita Rauth
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center at Omaha, Omaha, NE, USA
- Koelina Ganguly
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center at Omaha, Omaha, NE, USA
- Pranita Atri
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center at Omaha, Omaha, NE, USA
- Seema Parte
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center at Omaha, Omaha, NE, USA
- Rama Krishna Nimmakayala
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center at Omaha, Omaha, NE, USA
- Venkatesh Varadharaj
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center at Omaha, Omaha, NE, USA
- Palanisamy Nallasamy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center at Omaha, Omaha, NE, USA
- Raghupathy Vengoji
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center at Omaha, Omaha, NE, USA
- Ayoola O. Ogunleye
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center at Omaha, Omaha, NE, USA
- Imayavaramban Lakshmanan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center at Omaha, Omaha, NE, USA
- Ramakanth Chirravuri
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center at Omaha, Omaha, NE, USA
- Mika Bessho
- Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center at Omaha, Omaha, NE, USA
- Jesse L. Cox
- Department of Pathology and Microbiology, University of Nebraska Medical Center at Omaha, Omaha, NE, USA
- Jason M. Foster
- Department of Surgery, University of Nebraska Medical Center at Omaha, Omaha, NE, USA
- Geoffrey A. Talmon
- Department of Pathology and Microbiology, University of Nebraska Medical Center at Omaha, Omaha, NE, USA
- Tadayoshi Bessho
- Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center at Omaha, Omaha, NE, USA
- Apar Kishor Ganti
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center at Omaha, Omaha, NE, USA; Division of Oncology-Hematology, Department of Internal Medicine, VA Nebraska Western Iowa Health Care System, University of Nebraska Medical Center, Omaha, NE, USA; Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center at Omaha, Omaha, NE, USA
- Surinder K. Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center at Omaha, Omaha, NE, USA; Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center at Omaha, Omaha, NE, USA; Corresponding author
- Moorthy P. Ponnusamy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center at Omaha, Omaha, NE, USA; Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center at Omaha, Omaha, NE, USA; Corresponding author
- Journal volume & issue
-
Vol. 42,
no. 2
p. 112043
Abstract
Summary: Cisplatin- and gemcitabine-based chemotherapeutics represent a mainstay of cancer therapy for most solid tumors; however, resistance limits their curative potential. Here, we identify RNA polymerase II-associated factor 1 (PAF1) as a common driver of cisplatin and gemcitabine resistance in human cancers (ovarian, lung, and pancreas). Mechanistically, cisplatin- and gemcitabine-resistant cells show enhanced DNA repair, which is inhibited by PAF1 silencing. We demonstrate an increased interaction of PAF1 with RAD52 in resistant cells. Targeting the PAF1 and RAD52 axis combined with cisplatin or gemcitabine strongly diminishes the survival potential of resistant cells. Overall, this study shows clinical evidence that the expression of PAF1 contributes to chemotherapy resistance and worse clinical outcome for lethal cancers.
