Dataset Information

(-)-Sativan Inhibits Tumor Development and Regulates miR-200c/PD-L1 in Triple Negative Breast Cancer Cells.

ABSTRACT: Epithelial-to-mesenchymal transition (EMT) in cancer cells could convert epithelial-like cells to mesenchymal-like cells, resulting in the increased capacity of migration and invasion of cancer cells, and is an essential step in triple negative breast cancer (TNBC) development. Recent reports exert that these EMT-activated TNBC cells are more resistant to immune attacks, with high levels of programmed death ligand1 (PD-L1). Hence, it is worthwhile to find an effective approach in inhibiting EMT-activated TNBC cells. (-)-Sativan (SA) is a naturally isolated isoflavane and could be isolated from Spatholobus suberectus, a common traditional Chinese medicine used for breast cancer treatment. It was the first time that SA exerted anti-cancer effects on breast cancer cells, according to our study. In this study, SA displayed a significant inhibitory effect on the proliferation of TNBC cells by inducing apoptosis. SA increased Bax expression, and decreased Bcl-2 protein levels. SA inhibited cell migration and invasion of MDA-MB-231 and BT-549 cells. SA could decrease N-cadherin, Snail, Vimentin, and PD-L1 expression. SA increased miR-200c expression, and decreased PD-L1 expression. Luciferase assay showed that miR-200c directly targeted PD-L1. SA promoted tumor cell susceptibility to CTL-mediated lysis. Further study confirmed that SA could inhibit PD-L1 expression and EMT by up-regulating miR-200c. In vivo results displayed that SA could also inhibit tumor volumes and weights. These findings indicate that SA exerts an inhibitory effect on TNBC cell proliferation, migration, invasion, and tumor gtrowth, and partly provide evidence for the anti-breast cancer effect of Spatholobus suberectus Dunn in TNBC therapy.

SUBMITTER: Peng F

PROVIDER: S-EPMC7082844 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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(-)-Sativan Inhibits Tumor Development and Regulates miR-200c/PD-L1 in Triple Negative Breast Cancer Cells.

Peng Fu F Xiong Liang L Peng Cheng C

Frontiers in pharmacology 20200313

Epithelial-to-mesenchymal transition (EMT) in cancer cells could convert epithelial-like cells to mesenchymal-like cells, resulting in the increased capacity of migration and invasion of cancer cells, and is an essential step in triple negative breast cancer (TNBC) development. Recent reports exert that these EMT-activated TNBC cells are more resistant to immune attacks, with high levels of programmed death ligand1 (PD-L1). Hence, it is worthwhile to find an effective approach in inhibiting EMT- ...[more]

PMID: 32231566

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Project description:Immune checkpoint inhibitors (ICI), pembrolizumab and atezolizumab, were recently approved for treatment-refractory triple-negative breast cancer (TNBC), where those with Programmed death-ligand 1 (PD-L1) positive early-stage disease had improved responses. ICIs are administered systemically in the clinic, however, reaching effective therapeutic dosing is challenging due to severe off-tumor toxicities. As such, intratumoral (IT) injection is increasingly investigated as an alternative delivery approach. However, repeated administration, which sometimes is invasive, is required due to rapid drug clearance from the tumor caused by increased interstitial fluid pressure. To minimize off-target drug biodistribution, we developed the nanofluidic drug-eluting seed (NDES) platform for sustained intratumoral release of therapeutic via molecular diffusion. Here we compared drug biodistribution between the NDES, intraperitoneal (IP) and intratumoral (IT) injection using fluorescently labeled PD-L1 monoclonal antibody (αPD-L1). We used two syngeneic TNBC murine models, EMT6 and 4T1, that differ in PD-L1 expression, immunogenicity, and transport phenotype. We investigated on-target (tumor) and off-target distribution using different treatment approaches. As radiotherapy is increasingly used in combination with immunotherapy, we sought to investigate its effect on αPD-L1 tumor accumulation and systemic distribution. The NDES-treated cohort displayed sustained levels of αPD-L1 in the tumor over the study period of 14 days with significantly lower off-target organ distribution, compared to the IP or IT injection. However, we observed differences in the biodistribution of αPD-L1 across tumor models and with radiation pretreatment. Thus, we sought to extensively characterize the tumor properties via histological analysis, diffusion evaluation and nanoparticles contrast-enhanced CT. Overall, we demonstrate that ICI delivery via NDES is an effective method for sustained on-target tumor delivery across tumor models and combination treatments.

Project description:(1) Background: Triple-negative breast cancer (TNBC) is a distinct subgroup of breast cancer presenting a high level of recurrence, and neo-adjuvant chemotherapy is beneficial in its therapy management. Anti-PD-L1 immunotherapy improves the effect of neo-adjuvant therapy in TNBC. (2) Methods: Immune-modulation and ferroptosis-related R-packages were developed for integrative omics analyses under ferroptosis-inducer treatments: TNBC cells stimulated with ferroptosis inducers (GSE173905, GSE154425), single cell data (GSE191246) and mass spectrometry on breast cancer stem cells. Clinical association analyses were carried out with breast tumors (TCGA and METABRIC cohorts). Protein-level validation was investigated through protein atlas proteome experiments. (3) Results: Erastin/RSL3 ferroptosis inducers upregulate CD274 in TNBC cells (MDA-MB-231 and HCC38). In breast cancer, CD274 expression is associated with overall survival. Breast tumors presenting high expression of CD274 upregulated some ferroptosis drivers associated with prognosis: IDO1, IFNG and TNFAIP3. At the protein level, the induction of Cd274 and Tnfaip3 was confirmed in breast cancer stem cells under salinomycin treatment. In a 4T1 tumor treated with cyclophosphamide, the single cell expression of Cd274 was found to increase both in myeloid- and lymphoid-infiltrated cells, independently of its receptor Pdcd1. The CD274 ferroptosis-driver score computed on a breast tumor transcriptome stratified patients on their prognosis: low score was observed in the basal subgroup, with a higher level of recurrent risk scores (oncotypeDx, ggi and gene70 scores). In the METABRIC cohort, CD274, IDO1, IFNG and TNFAIP3 were found to be overexpressed in the TNBC subgroup. The CD274 ferroptosis-driver score was found to be associated with overall survival, independently of TNM classification and age diagnosis. The tumor expression of CD274, TNFAIP3, IFNG and IDO1, in a biopsy of breast ductal carcinoma, was confirmed at the protein level (4) Conclusions: Ferroptosis inducers upregulate PD-L1 in TNBC cells, known to be an effective target of immunotherapy in high-risk early TNBC patients who received neo-adjuvant therapy. Basal and TNBC tumors highly expressed CD274 and ferroptosis drivers: IFNG, TNFAIP3 and IDO1. The CD274 ferroptosis-driver score is associated with prognosis and to the risk of recurrence in breast cancer. A potential synergy of ferroptosis inducers with anti-PD-L1 immunotherapy is suggested for recurrent TNBC.

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(-)-Sativan Inhibits Tumor Development and Regulates miR-200c/PD-L1 in Triple Negative Breast Cancer Cells.

Publications

(-)-Sativan Inhibits Tumor Development and Regulates miR-200c/PD-L1 in Triple Negative Breast Cancer Cells.

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