ABSTRACT
Visible light-induced aza-6π electrocyclization was developed for the synthesis of aza-arenes from nitroarenes with diverse aldehydes. This protocol allows the reduction of nitroarenes by B2nep2 and subsequent 6π-electrocyclization of the in situ formed imine under visible light. An array of 6- and multi-substituted phenanthridines were constructed in moderate to good yields under purple LEDs at room temperature. A wide scope of substrates with diverse functional groups were well tolerated. In addition, the synthetic utility of this methodology was further demonstrated in the late-stage functionalization of celecoxib.
ABSTRACT
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and it lacks specific therapeutic targets and effective treatment protocols. By analyzing a proteomic TNBC dataset, we found significant upregulation of sideroflexin 1 (SFXN1) in tumor tissues. However, the precise function of SFXN1 in TNBC remains unclear. Immunoblotting was performed to determine SFXN1 expression levels. Label-free quantitative proteomics and liquid chromatography-tandem mass spectrometry were used to identify the downstream targets of SFXN1. Mechanistic studies of SFXN1 and cellular inhibitor of PP2A (CIP2A) were performed using immunoblotting, immunofluorescence staining, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Functional experiments were used to investigate the role of SFXN1 in TNBC cells. SFXN1 was significantly overexpressed in TNBC tumor tissues and was associated with unfavorable outcomes in patients with TNBC. Functional experiments demonstrated that SFXN1 promoted TNBC growth and metastasis in vitro and in vivo. Mechanistic studies revealed that SFXN1 promoted TNBC progression by inhibiting the autophagy receptor TOLLIP (toll interacting protein)-mediated autophagic degradation of CIP2A. The pro-tumorigenic effect of SFXN1 overexpression was partially prevented by lapatinib-mediated inhibition of the CIP2A/PP2A/p-AKT pathway. These findings may provide a new targeted therapy for patients with TNBC.
Subject(s)
Autoantigens , Autophagy , Cation Transport Proteins , Lapatinib , Membrane Proteins , Triple Negative Breast Neoplasms , Animals , Female , Humans , Mice , Antineoplastic Agents/pharmacology , Autoantigens/metabolism , Autoantigens/genetics , Autophagy/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Disease Progression , Gene Expression Regulation, Neoplastic/drug effects , Intracellular Signaling Peptides and Proteins/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Lapatinib/pharmacology , Membrane Proteins/metabolism , Membrane Proteins/genetics , Proteolysis/drug effects , Signal Transduction/drug effects , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/genetics , Xenograft Model Antitumor Assays , Cation Transport Proteins/genetics , Cation Transport Proteins/metabolismABSTRACT
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Transcriptional dysregulation is a hallmark of cancer, and several transcriptional regulators have been demonstrated to contribute to cancer progression. In this study, we identified an upregulation of the transcriptional corepressor downregulator of transcription 1-associated protein 1 (DRAP1) in TNBC, which was closely associated with poor recurrence-free survival in patients with TNBC. DRAP1 promoted TNBC proliferation, migration, and invasion in vitro and tumor growth and metastasis in vivo. Mechanistically, the downregulator of transcription 1 (DR1)/DRAP1 heterodimer complex inhibited expression of the cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1) and thereby increased activation of mTOR, which sensitized TNBC to treatment with the mTOR inhibitor everolimus. DRAP1 and DR1 also formed a positive feedback loop. DRAP1 enhanced the stability of DR1 by recruiting the deubiquitinase USP7 to inhibit its proteasomal degradation; in turn, DR1 directly promoted DRAP1 transcription. Collectively, this study uncovered a DRAP1-DR1 bidirectional regulatory pathway that promotes TNBC progression, suggesting that targeting the DRAP1/DR1 complex might be a potential therapeutic strategy to treat TNBC. Significance: DR1 and DRAP1 form a positive feedback loop and a repressor complex to cooperatively inhibit cytosolic arginine sensor for mTORC1 subunit 1 transcription and stimulate mTOR signaling, leading to progression and increased everolimus sensitivity in triple-negative breast cancer.
Subject(s)
Disease Progression , Everolimus , TOR Serine-Threonine Kinases , Triple Negative Breast Neoplasms , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/genetics , Humans , Female , TOR Serine-Threonine Kinases/metabolism , Everolimus/pharmacology , Animals , Mice , Cell Proliferation/drug effects , Cell Line, Tumor , Gene Expression Regulation, Neoplastic/drug effects , Xenograft Model Antitumor Assays , Mice, Nude , Cell Movement/drug effects , Mice, Inbred BALB CABSTRACT
Triple-negative breast cancer (TNBC) is the deadliest subtype of breast cancer owing to the lack of effective therapeutic targets. Splicing factor 3a subunit 2 (SF3A2), a poorly defined splicing factor, was notably elevated in TNBC tissues and promoted TNBC progression, as confirmed by cell proliferation, colony formation, transwell migration, and invasion assays. Mechanistic investigations revealed that E3 ubiquitin-protein ligase UBR5 promoted the ubiquitination-dependent degradation of SF3A2, which in turn regulated UBR5, thus forming a feedback loop to balance these two oncoproteins. Moreover, SF3A2 accelerated TNBC progression by, at least in part, specifically regulating the alternative splicing of makorin ring finger protein 1 (MKRN1) and promoting the expression of the dominant and oncogenic isoform, MKRN1-T1. Furthermore, SF3A2 participated in the regulation of both extrinsic and intrinsic apoptosis, leading to cisplatin resistance in TNBC cells. Collectively, these findings reveal a previously unknown role of SF3A2 in TNBC progression and cisplatin resistance, highlighting SF3A2 as a potential therapeutic target for patients with TNBC.
Subject(s)
Cisplatin , Triple Negative Breast Neoplasms , Humans , Cisplatin/pharmacology , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/metabolism , Alternative Splicing , Cell Line, Tumor , Cell Proliferation , Gene Expression Regulation, Neoplastic , RNA Splicing Factors/genetics , RNA Splicing Factors/metabolismABSTRACT
An efficient method was developed for the one-pot construction of C-B and C-I via visible light-induced transformation of nitroarenes. This protocol relies on the photochemical properties of nitroarenes under visible light, followed by reduction with B2pin2 and diazotization with tBuONO. An array of arylboronates and iodobenzenes were constructed smoothly after excitation with purple LEDs at room temperature. In addition, the synthetic utility of this method was further demonstrated in the late-stage modification of a drug molecule. The advantages of this strategy include metal-free system, mild reaction conditions and acceptable substrate scope.
ABSTRACT
Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer with no targeted therapy. Spermatid perinuclear RNA binding protein (STRBP), a poorly characterized RNA-binding protein (RBP), has an essential role in normal spermatogenesis and sperm function, but whether and how its dysregulation contributing to cancer progression has not yet been explored. Here, we report that STRBP functions as a novel oncogene to drive TNBC progression. STRBP expression was upregulated in TNBC tissues and correlated with poor disease prognosis. Functionally, STRBP promoted TNBC cell proliferation, migration, and invasion in vitro, and enhanced xenograft tumor growth and lung colonization in mice. Mechanistically, STRBP interacted with Dicer, a core component of the microRNA biogenesis machinery, and promoted its proteasomal degradation through enhancing its interaction with E3 ubiquitin ligase UBR5. MicroRNA-sequencing analysis identified miR-200a-3p as a downstream effector of STRBP, which was regulated by Dicer and affected epithelial-mesenchymal transition. Importantly, the impaired malignant phenotypes of TNBC cells caused by STRBP depletion were largely rescued by knockdown of Dicer, and these effects were compromised by transfection of miR-200a-3p mimics. Collectively, these findings revealed a previously unrecognized oncogenic role of STRBP in TNBC progression and identified STRBP as a promising target against TNBC.
Subject(s)
MicroRNAs , Triple Negative Breast Neoplasms , Animals , Humans , Male , Mice , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic , MicroRNAs/genetics , MicroRNAs/metabolism , Proteolysis , Semen/metabolism , Spermatids/metabolism , Spermatids/pathology , Triple Negative Breast Neoplasms/pathology , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolismABSTRACT
We developed a visible-light-driven expanded EDA complex profile for the synthesis of aza-arenes via aza-6π electrocyclization of 2-styrylanilines with aromatic aldehydes. This protocol relies on the EDA complexes of AlCl3 with imine to induce the absorption red-shift to visible light from ultraviolet light. An array of 2,3-disubstituted quinolines were constructed smoothly after excitation with blue-light-emitting diodes at room temperature. In addition, the resultant product, used as a cell permeable lipid droplet-specific probe, shows a low working concentration, a short staining time, and functionality in living and fixed cells.