Nuclear cathepsin L induces DNA damage by regulating DNA repair factors in ovarian cancer
4 affiliations
- 1Department of Experimental Pathology and Medicine, Mayo Clinic, Rochester, MN USA
- 2Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, CA USA
- 3University of Connecticut Health Center-Medical School, Farmington, CT USA
- 4Department of Oncology, Mayo Clinic, Rochester, MN USA
Abstract
Resistance to PARP inhibitors (PARPi) remains a major clinical challenge in ovarian cancer (OC), emphasizing the need for novel strategies to enhance therapeutic efficiency. Our previous work revealed that the antimalarial drug quinacrine (QC) can be repurposed to induce cell death in OC by promoting lysosomal release of active cathepsin L (CTSL). Building on these outcomes, we investigated whether QC-activated CTSL influences DNA damage and homologous recombination (HR) repair in OC cells. Our experimental evidence shows that QC-activated CTSL downregulates key DNA repair proteins RAD51 and 53BP1, leading to impaired HR repair and increased DNA damage. Importantly, genetic knockdown of CTSL significantly reduced QC-induced DNA damage, confirming the CTSL plays a direct functional role in this process. We also found out that the response of combined QC and PARPi differs in models. CTSL was translocated to the nucleus (nCTSL) in responsive patient-derived ascitic (PDA) and patient-derived xenograft (PDX) spheroids. Contrarily, non-responsive models did not have nuclear CTSL. Mechanically, QC could not suppress CRM1/XPO1 nuclear export receptor in non-responsive cells, leading to continued export of CTSL from the nucleus. To address this, we have used the CRM1 inhibitor KPT-8602, which restored nuclear retention of CTSL. This led to enhanced therapeutic synergy with PARPi and overcame resistance in QC-treated PDA 3D-spheroids. Consistent with these findings, QC reduced tumor burden in both the cell-derived OVCAR-5 xenograft and PDX-PH070 models that showed QC-induced nCTSL, but not in the non-responsive PDX-PH095 model. However, in additional non-responsive PDX models (PH747 and PH081), treatment with QC and KPT-8602 substantially reduced tumor burden. Collectively, our results confirm a critical role for nuclear CTSL in QC-induced DNA damage and identify nCTSL as a possible predictive biomarker of therapeutic response. These results suggest that combining QC with PARPi or CRM1 inhibitors represents a promising strategy to overcome PARPi resistance in OC.
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BibTeX
@article{thirusangu2026nuclear,
title = {{Nuclear cathepsin L induces DNA damage by regulating DNA repair factors in ovarian cancer}},
author = {Prabhu Thirusangu and Upasana Ray and Ling Jin and Biswajit Das and Christopher L. Pathoulas and Julie Staub and Ann L. Oberg and Xiaonan Hou and Jamison L. VanBlaricom and Nagarajan Kannan and John Weroha and Jamie N. Bakkum-Gamez and Viji Shridhar},
journal = {Oncogene},
year = {2026},
month = oct,
doi = {10.1038/s41388-026-04001-6},
url = {https://doi.org/10.1038/s41388-026-04001-6},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Nuclear cathepsin L induces DNA damage by regulating DNA repair factors in ovarian cancer
AU - Prabhu Thirusangu
AU - Upasana Ray
AU - Ling Jin
AU - Biswajit Das
AU - Christopher L. Pathoulas
AU - Julie Staub
AU - Ann L. Oberg
AU - Xiaonan Hou
AU - Jamison L. VanBlaricom
AU - Nagarajan Kannan
AU - John Weroha
AU - Jamie N. Bakkum-Gamez
AU - Viji Shridhar
PY - 2026
DA - 2026/10/01
JO - Oncogene
DO - 10.1038/s41388-026-04001-6
UR - https://doi.org/10.1038/s41388-026-04001-6
AB - Resistance to PARP inhibitors (PARPi) remains a major clinical challenge in ovarian cancer (OC), emphasizing the need for novel strategies to enhance therapeutic efficiency. Our previous work revealed that the antimalarial drug quinacrine (QC) can be repurposed to induce cell death in OC by promoting lysosomal release of active cathepsin L (CTSL). Building on these outcomes, we investigated whether QC-activated CTSL influences DNA damage and homologous recombination (HR) repair in OC cells. Our experimental evidence shows that QC-activated CTSL downregulates key DNA repair proteins RAD51 and 53BP1, leading to impaired HR repair and increased DNA damage. Importantly, genetic knockdown of CTSL significantly reduced QC-induced DNA damage, confirming the CTSL plays a direct functional role in this process. We also found out that the response of combined QC and PARPi differs in models. CTSL was translocated to the nucleus (nCTSL) in responsive patient-derived ascitic (PDA) and patient-derived xenograft (PDX) spheroids. Contrarily, non-responsive models did not have nuclear CTSL. Mechanically, QC could not suppress CRM1/XPO1 nuclear export receptor in non-responsive cells, leading to continued export of CTSL from the nucleus. To address this, we have used the CRM1 inhibitor KPT-8602, which restored nuclear retention of CTSL. This led to enhanced therapeutic synergy with PARPi and overcame resistance in QC-treated PDA 3D-spheroids. Consistent with these findings, QC reduced tumor burden in both the cell-derived OVCAR-5 xenograft and PDX-PH070 models that showed QC-induced nCTSL, but not in the non-responsive PDX-PH095 model. However, in additional non-responsive PDX models (PH747 and PH081), treatment with QC and KPT-8602 substantially reduced tumor burden. Collectively, our results confirm a critical role for nuclear CTSL in QC-induced DNA damage and identify nCTSL as a possible predictive biomarker of therapeutic response. These results suggest that combining QC with PARPi or CRM1 inhibitors represents a promising strategy to overcome PARPi resistance in OC.
SN - 0950-9232
SN - 1476-5594
ER -