Investigator

Guo Chen

Professor · China Pharmaceutical University, School of Bioparmacy

GCGuo Chen
Papers(3)
Natural product Pulsa…Targeting GPX4-mediat…SN-38 Sensitizes BRCA…
Collaborators(4)
Shengbin LinXiao LiYongzhu LiuFan Zhang
Institutions(5)
China Pharmaceutical …Jinan UniversitySoutheast UniversityGuangzhou Medical Uni…Fudan University

Papers

Natural product Pulsatilla saponin D sensitizes BRCA-proficient ovarian cancers to PARP inhibitors through inhibiting homologous recombination repair

Abstract Background As a strategy in the development of effective cancer therapeutics, synthetic lethality has been used in clinical practice. Poly adenosine diphosphate (ADP)-ribose polymerase inhibitors are the first approved drug utilized synthetic lethality and achieved promising therapeutic efficacy in cancer cells with BRCA1/2 mutation. Nonetheless, most cancer patients with wild-type BRCA1/2 gene are not qualified for PARPi therapy. To induce BRCAness phenotype in cancer cells with normal BRCA1/2 status, we identified Pulsatilla Saponin D (SB365), which efficiently inhibited recruitment of BRCA1 at DNA double-strand breaks, leading to homologous recombination repair deficiency. Methods We utilized the HR repair reporter system. The reporter cells were treated with a natural compounds library to identify the agent that significantly decreased HR activity. Then, we detected the expression of HR related proteins using immunofluorescence and western blot. Colony formation and CCK8 was used to detect the inhibitory effect of Pulsatilla Saponin D on cell proliferation. Apoptosis was measured using Annexin V/PI staining. Comet assay kits were used to carry out the comet assay. Ovarian cancer xenograft model, immunohistochemical staining and Hematoxylin-Eosin staining was used to detect the antitumor efficacy and toxicity of Pulsatilla Saponin D. Key findings Pulsatilla Saponin D greatly increased PARPi-induced DNA DSBs, growth inhibition and apoptosis in ovarian cancer cells. Combined administration of PARPi and Pulsatilla Saponin D induced synergistic anti-tumor effects in ovarian cancer cells and xenograft mouse model without obvious toxicity. Conclusions In summary, our study found Pulsatilla Saponin D is a novel HR repair inhibitor and would optimize clinical application of PARP inhibitors on cancer patients with WT BRCA1/2.

Targeting GPX4-mediated ferroptosis protection sensitizes BRCA1-deficient cancer cells to PARP inhibitors

BRCA1 is one of the most frequently-mutated tumor suppressor genes in ovarian and breast cancers. Loss of BRCA1 triggers homologous recombination (HR) repair deficiency, consequently leading to genomic instability and PARP inhibitors (PARPi)-associated synthetic lethality. Although, the roles of BRCA1 in DNA repair and replication have been extensively investigated, its tumor suppressive functions beyond genome safeguard remain poorly understood. Here, we report that BRCA1 promotes ferroptosis susceptibility through catalyzing K6-linked polyubiquitination of GPX4 and subsequently accelerating GPX4 degradation. Depletion of BRCA1 induces ferroptosis resistance in ovarian cancer cells due to elevated GPX4 protein, and silence of GPX4 significantly suppresses the growth of BRCA1-deficient ovarian cancer xenografts. Importantly, we found that PARPi triggers ferroptosis in ovarian cancer cells, inhibition of GPX4 markedly increase PARPi-induced ferroptosis in BRCA1-deficient ovarian cancer cells. Combined treatment of GPX4 inhibitor and PARPi produces synergistic anti-tumor efficacy in BRCA1-deficient ovarian cancer cells, patient derived organoid (PDO) and xenografts. Thus, our study uncovers a novel mechanism via which BRCA1 exerts tumor suppressive function through regulating ferroptosis, and demonstrates the potential of GPX4 as a therapeutic target for BRCA1-mutant cancers.

59Works
3Papers
4Collaborators
Cell Line, TumorApoptosisOvarian NeoplasmsLeukemia, Myeloid, AcuteApoptosis Regulatory ProteinsCarcinoma, Ovarian Epithelial

Positions

2022–

Professor

China Pharmaceutical University · School of Bioparmacy

2019–

Professor

Jinan University

2012–

Postdoctoral fellow

Emory University

Education

2012

Postdoctoral fellow

Emory University · Radiation Oncology

2012

Ph.D

Nanjing University · Biochemistry

2006

Bachelor of Science

Huazhong Agriculture University