Therapy-induced senescence (TIS) is common in tumor cells treated with PARP inhibitors (PARPis) and can serve as a promising target for improving PARPi efficacy. However, whether stromal components within the tumor microenvironment undergo TIS caused by PARPis and contribute to consequential treatment failure remain unclear. We previously revealed that PARPis triggered a senescence-like secretory phenotype in stromal fibroblasts. Here, we further explored PARPi-induced senescence in the stroma, its contribution to PARPi resistance, and opportunities to leverage stromal TIS for improved PARPi sensitivity. In this study, we demonstrated that tumor tissues from patients treated with neoadjuvant PARPis showed a significant senescence-like phenotype in the stroma. Moreover, PARPi-induced senescent cancer-associated fibroblasts (CAFs) displayed a senescence-associated secretory phenotype (SASP) profile that was sufficient to induce tumor resistance to PARPis in both homologous recombination-deficient (HRD) and -proficient ovarian cancer cells. Using the GLAD4U database, we found that bepotastine, an approved H1-antihistamine, inhibited the SASP of PARPi-primed CAFs at clinical serum concentrations. We further demonstrated that bepotastine attenuated fibroblast-facilitated tumor resistance to PARPis in three-dimensional organotypic cultures and HRD-positive patient-derived xenograft models. Mechanistically, bepotastine suppressed PARPi-triggered SASP by inhibiting NF-κB signaling independent of the histamine H1 receptor. Taken together, our results highlight the importance of stromal TIS and SASP in PARPi resistance, and targeting SASP with bepotastine may be a promising therapeutic option for improving PARPi sensitivity in ovarian cancer.
<div>Abstract<p>Therapy-induced senescence (TIS) is common in tumor cells treated with PARP inhibitors (PARPis) and can serve as a promising target for improving PARPi efficacy. However, whether stromal components within the tumor microenvironment undergo TIS caused by PARPis and contribute to consequential treatment failure remain unclear. We previously revealed that PARPis triggered a senescence-like secretory phenotype in stromal fibroblasts. Here, we further explored PARPi-induced senescence in the stroma, its contribution to PARPi resistance, and opportunities to leverage stromal TIS for improved PARPi sensitivity. In this study, we demonstrated that tumor tissues from patients treated with neoadjuvant PARPis showed a significant senescence-like phenotype in the stroma. Moreover, PARPi-induced senescent cancer-associated fibroblasts (CAFs) displayed a senescence-associated secretory phenotype (SASP) profile that was sufficient to induce tumor resistance to PARPis in both homologous recombination–deficient (HRD) and –proficient ovarian cancer cells. Using the GLAD4U database, we found that bepotastine, an approved H1-antihistamine, inhibited the SASP of PARPi-primed CAFs at clinical serum concentrations. We further demonstrated that bepotastine attenuated fibroblast-facilitated tumor resistance to PARPis in three-dimensional organotypic cultures and HRD-positive patient-derived xenograft models. Mechanistically, bepotastine suppressed PARPi-triggered SASP by inhibiting NF-κB signaling independent of the histamine H1 receptor. Taken together, our results highlight the importance of stromal TIS and SASP in PARPi resistance, and targeting SASP with bepotastine may be a promising therapeutic option for improving PARPi sensitivity in ovarian cancer.</p></div>
Abstract Background UQCRFS1 is a crucial subunit of mitochondrial compound III, which mediates the mitochondrial electron transfer process. Although the gene has been reported to be highly expressed in gastric and breast cancer, the prognosis and biological functions of UQCRFS1 in ovarian cancer have not been evaluated. Methods UQCRFS1 mRNA and protein expression levels were determined using the Human Protein Atlas (HPA) database and Gene Expression Profiling Interactive Analysis (GEPIA). Western blotting and immunohistochemistry were used for validation. The effect of prognosis was investigated based on the cancer genome atlas (TCGA) database. The correlation with tumor-related signature was evaluated based on c-BioPortal database. Knockdown cell lines were further constructed to verify the biological effect of this gene. Total and phosphorylated levels of AKT and mTOR were analysed by western blotting. Results GEPIA and HAP analysis revealed that UQCRFS1 was overexpressed in ovarian cancer compared with normal tissues, which was associated with poor prognosis in ovarian cancer patients. Western blotting and immunohistochemistry also confirmed this finding. Correlation analysis showed that UQCRFS1 overexpression was positively correlated with cycle and oxidative phosphorylation signature, and negatively correlated with apoptosis and DNA damage. Functional analysis showed that UQCRFS1 knockdown resulted in attenuated ovarian cancer cell proliferation, increased G1 phase, and increased apoptosis rate. In addition, mRNA expression of DNA damage genes increased, ROS levels increased, and total AKT and mTOR levels and phosphorylation levels decreased. Conclusions UQCRFS1 is overexpressed in ovarian cancer and is associated with poor prognosis. UQCRFS1 affects ovarian cell survival by affecting proliferation, cell cycle, DNA damage and ROS levels, which may be attributed to the AKT/mTOR pathway.
Abstract Background Ovarian cancer (OC) patients benefited little from systematic pelvic/para-aortic lymph node dissection during surgery, which may attribute to the difficulties in identifying the patients with pelvic/para-aortic lymph node metastases (LNM) preoperatively. Unfortunately, risk factors predicting the pelvic/para-aortic LNM in OC patients are lacking now. The purpose of this study was to investigate preoperative risk factors of predicting OC patients at high risk of pelvic/para-aortic LNM and preventing OC patients at low risk of LNM from receiving unnecessary lymphadenectomy. Methods Patients diagnosed with OC between January 2012 and May 2020 from Tongji Hospital, Chongqing Cancer Hospital, and Tumor Hospital of Henan, were retrospectively reviewed. Demographics, pathology, and preoperative laboratory features were extracted from Electronic-Medical Records. The correlation between factors and LNM was assessed by chi-square test and multivariate logistic regression analysis. Results A total of 827 patients were included in this study. Univariate analysis indicated 23 preoperative features were significantly associated with LNM. Multivariate analysis showed that BMI ≥ 23.23 kg/m 2 (odds ratio [OR], 2.082; 95% confidence interval [CI], 1.448–2.995), ascites (OR, 3.022, 95% CI, 2.058–4.438), CA125 ≥ 432.15 U/ml (OR, 4.665, 95% CI, 3.158–6.891), neutrophil count ≥ 2.965*10 9 /L (OR, 2.882, 95% CI, 1.606–5.172), lymphocyte count < 1.30*10 9 /L (OR, 1.554, 95% CI, 1.086–2.223), and monocyte count ≥ 0.415*10 9 /L (OR, 1.506, 95% CI, 1.047–2.166) were independent risk factors in predicting LNM. The area under the curve (AUC) of predicting LNM by combining these factors was 0.836 (95% CI 0.808–0.864). The predicting performance of this model was also promising in OC patients with early-stage (stage I-II) (AUC, 0.809, 95% CI, 0.619–1.000) and advanced-stage (stage III-IV) (AUC, 0.764, 95% CI, 0.723–0.805). Furthermore, patients with 0–3 risk factors had significantly lower LNM rates than those of patients with 4–6 risk factors (15.40% vs 58.92%, p < 0.001). Conclusions Preoperative BMI, ascites, CA125 level, neutrophil count, lymphocyte count, and monocyte count can predict the risk of LNM and facilitate decision-making of systematic lymphadenectomy in OC patients, which could avoid unnecessary lymphadenectomy.
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