Lutetium Texaphyrin-Celecoxib Conjugate as a Potential Immuno-Photodynamic Therapy Agent.

Immuno-photodynamic therapy (IPDT) has emerged as a new modality for cancer treatment. Novel photosensitizers can help achieve the promise inherent in IPDT, namely, the complete eradication of a tumor without recurrence. We report here a small molecule photosensitizer conjugate, LuCXB. This IPDT agent integrates a celecoxib (cyclooxygenase-2 inhibitor) moiety with a near-infrared absorbing lutetium texaphyrin photocatalytic core. In aqueous environments, the two components of LuCXB are self-associated through inferred donor-acceptor interactions. A consequence of this intramolecular association is that upon photoirradiation with 730 nm light, LuCXB produces superoxide radicals (O2-•) via a type I photodynamic pathway; this provides a first line of defense against the tumor while promoting IPDT. For in vivo therapeutic applications, we prepared a CD133-targeting, aptamer-functionalized exosome-based nanophotosensitizer (Ex-apt@LuCXB) designed to target cancer stem cells. Ex-apt@LuCXB was found to display good photosensitivity, acceptable biocompatibility, and robust tumor targetability. Under conditions of photoirradiation, Ex-apt@LuCXB acts to amplify IPDT while exerting a significant antitumor effect in both liver and breast cancer mouse models. The observed therapeutic effects are attributed to a synergistic mechanism that combines antiangiogenesis and photoinduced cancer immunotherapy.

Photosensitive and dual-targeted chromium nanoparticle delivering small interfering RNA YTHDF1 for molecular-targeted immunotherapy in liver cancer.

Tumor-associated macrophages (TAMs) are a promising target for cancer immunotherapy, but delivering therapeutic agents to TAMs within the tumor microenvironment (TME) is challenging. In this study, a photosensitive, dual-targeting nanoparticle system (M.RGD@Cr-CTS-siYTHDF1 NPs) was developed. The structure includes a shell of DSPE-modified RGD peptides targeting integrin receptors on tumor cells and carboxymethyl mannose targeting CD206 receptors on macrophages, with a core of chitosan adsorbing m6A reading protein YTHDF1 siRNA and chromium nanoparticles (Cr NPs). The approach is specifically designed to target TAM and cancer cells, utilizing the photothermal effect of Cr NPs to disrupt the TME and deliver siYTHDF1 to TAM. In experiments with tumor-bearing mice, M.RGD@Cr-CTS-siYTHDF1 NPs, when exposed to laser irradiation, effectively killed tumor cells, disrupted the TME, delivered siYTHDF1 to TAMs, silenced the YTHDF1 gene, and shifted the STAT3-STAT1 equilibrium by reducing STAT3 and enhancing STAT1 expression. This reprogramming of TAMs towards an anti-tumor phenotype led to a pro-immunogenic TME state. The strategy also suppressed immunosuppressive IL-10 production, increased expression of immunostimulatory factors (IL-12 and IFN-γ), boosted CD8 + T cell infiltration and M1-type TAMs, and reduced Tregs and M2-type TAMs within the TME. In conclusion, the dual-targeting M.RGD@Cr-CTS-siYTHDF1 NPs, integrating dual-targeting capabilities with photothermal therapy (PTT) and RNA interference, offer a promising approach for molecular targeted cancer immunotherapy with potential for clinical application.

Targeted disruption of the BCR-ABL fusion gene by Cas9/dual-sgRNA inhibits proliferation and induces apoptosis in chronic myeloid leukemia cells.

The BCR-ABL fusion gene, formed by the fusion of the breakpoint cluster region protein ( BCR) and the Abl Oncogene 1, Receptor Tyrosine Kinase ( ABL) genes, encodes the BCR-ABL oncoprotein, which plays a crucial role in leukemogenesis. Current therapies have limited efficacy in patients with chronic myeloid leukemia (CML) because of drug resistance or disease relapse. Identification of novel strategies to treat CML is essential. This study aims to explore the efficiency of novel CRISPR-associated protein 9 (Cas9)/dual-single guide RNA (sgRNA)-mediated disruption of the BCR-ABL fusion gene by targeting BCR and cABL introns. A co-expression vector for Cas9 green fluorescent protein (GFP)/dual-BA-sgRNA targeting BCR and cABL introns is constructed to produce lentivirus to affect BCR-ABL expression in CML cells. The effects of dual-sgRNA virus-mediated disruption of BCR-ABL are analyzed via the use of a genomic sequence and at the protein expression level. Cell proliferation, cell clonogenic ability, and cell apoptosis are assessed after dual sgRNA virus infection, and phosphorylated BCR-ABL and its downstream signaling molecules are detected. These effects are further confirmed in a CML mouse model via tail vein injection of Cas9-GFP/dual-BA-sgRNA virus-infected cells and in primary cells isolated from patients with CML. Cas9-GFP/dual-BA-sgRNA efficiently disrupts BCR-ABL at the genomic sequence and gene expression levels in leukemia cells, leading to blockade of the BCR-ABL tyrosine kinase signaling pathway and disruption of its downstream molecules, followed by cell proliferation inhibition and cell apoptosis induction. This method prolongs the lifespan of CML model mice. Furthermore, the effect is confirmed in primary cells derived from patients with CML.

Fusobacterium nucleatum-derived small extracellular vesicles facilitate tumor growth and metastasis via TLR4 in breast cancer.

BACKGROUND: The contributive role of the microbiome in tumor progression has been reported in multiple studies, such as the Fusobacterium nucleatum (F. nucleatum) in breast cancer (BC). This study aimed to explore the role of F. nucleatum-derived small extracellular vesicles (Fn-EVs) in BC and preliminarily uncover the mechanism. METHODS: Ten normal and 20 cancerous breast tissues were harvested to investigate the gDNA expression of F. nucleatum and its relation with the clinical characteristics of BC patients. After isolating Fn-EVs by ultracentrifugation from F. nucleatum (ATCC 25,586), both MDA-MB-231 and MCF-7 cells were treated with PBS, Fn, or Fn-EVs, followed by being subjected to CCK-8, Edu staining, wound healing, and Transwell assays to detect their cell viability, proliferation, migration, and invasion. TLR4 expression in BC cells with diverse treatments was assessed by western blot. In vivo experiments were performed to verify its role in tumor growth and liver metastasis. RESULTS: The F. nucleatum gDNA levels of breast tissues in BC patients were significantly higher than those in normal subjects, and positively associated with tumor size and metastasis. Fn-EVs administration significantly enhanced the cell viability, proliferation, migration, and invasion of BC cells, while knocking down TLR4 in BC cells could block these effects. Furthermore, in vivo study verified the contributive role of Fn-EVs in tumor growth and metastasis of BC, which might rely on its regulation of TLR4. CONCLUSIONS: Collectively, our results suggest that F. nucleatum plays an important role in BC tumor growth and metastasis by regulating TLR4 through Fn-EVs. Thus, a better understanding of this process may aid in the development of novel therapeutic agents.

Kruppel-like factor 5 enhances proliferation, lipid droplet formation and oxaliplatin resistance in colorectal cancer by promoting fatty acid binding protein 6 transcription.

Oxaliplatin (OXA) is a standard agent for colorectal cancer (CRC) adjuvant chemotherapy. However, acquired and intrinsic OXA resistance is a primary challenge for CRC treatment. This study investigates the function of the Kruppel-like factor 5/fatty acid binding proteins 6 (KLF5/FABP6) axis in CRC proliferation, lipid droplet formation and OXA resistance. OXA-resistant CRC cell lines were constructed, and FABP6 and KLF5 expression was assessed in parental and OXA-resistant CRC cells. Subsequent to gain- and loss-of-function experiments, CRC cell proliferation was assessed by cell counting kit-8 (CCK-8) and clone formation assays, the intracellular lipid synthesis by oil red O staining and the protein expression of lipid metabolism genes by western blot. OXA resistance of CRC cells was assessed by CCK-8 assay. The binding of KLF5 to FABP6 was analyzed by the dual-luciferase reporter and ChIP assays. A tumorigenicity assay in nude mice was adopted to examine the impact of KLF5 on CRC tumor growth and OXA resistance in vivo . FABP6 and KLF5 expression was high in CRC cell lines. Downregulation of FABP6 or KLF5 restrained CRC cell proliferation and lipid droplet formation in vitro . FABP6 and KLF5 expression was elevated in OXA-resistant CRC cells. Downregulation of FABP6 or KLF5 repressed the OXA resistance of OXA-resistant CRC cells. Mechanistically, KLF5 facilitated the transcription of FABP6. FABP6 overexpression counteracted the suppressive effects of KLF5 downregulation on CRC cell growth, lipid droplet formation and OXA resistance. KLF5 downregulation restrained CRC tumor growth and OXA resistance in vivo . In conclusion, KLF5 knockdown reduced FABP6 transcription to protect against proliferation, lipid droplet formation and OXA resistance in CRC.

Stabilization of UCA1 by N6-methyladenosine RNA methylation modification promotes colorectal cancer progression.

BACKGROUND: UCA1 is frequently upregulated in a variety of cancers, including CRC, and it can play an oncogenic role by various mechanisms. However, how UCA1 is regulated in cancer is largely unknown. In this study, we aimed to determine whether RNA methylation at N6-methyladenosine (m6A) can impact UCA1 expression in colorectal cancer (CRC). METHODS: qRT-PCR was performed to detect the level of UCA1 and IGF2BP2 in CRC samples. CRISPR/Cas9 was employed to knockout (KO) UCA1, METTL3 and WTAP in DLD-1 and HCT-116 cells, while rescue experiments were carried out to re-express METTL3 and WTAP in KO cells. Immunoprecipitation using m6A antibody was performed to determine the m6A modification of UCA1. In vivo pulldown assays using S1m tagging combined with site-direct mutagenesis was carried out to confirm the recognition of m6A-modified UCA1 by IGF2BP2. Cell viability was measured by MTT and colony formation assays. The expression of UCA1 and IGF2BP2 in TCGA CRC database was obtained from GEPIA ( http://gepia.cancer-pku.cn ). RESULTS: Our results revealed that IGF2BP2 serves as a reader for m6A modified UCA1 and that adenosine at 1038 of UCA1 is critical to the recognition by IGF2BP2. Importantly, we showed that m6A writers, METTL3 and WTAP positively regulate UCA1 expression. Mechanically, IGF2BP2 increases the stability of m6A-modified UCA1. Clinically, IGF2BP2 is upregulated in CRC tissues compared with normal tissues. CONCLUSION: These results suggest that m6A modification is an important factor contributing to upregulation of UCA1 in CRC tissues.

AKR1B10 protects against UVC-induced DNA damage in breast cancer cells.

The cellular response to DNA damage is crucial for maintaining the integrity and stability of molecular structure. To maintain genome stability, DNA-damaged cells should be arrested so that mutations can be repaired before replication. Although several key components required for this arrest have been discovered, the majority of the pathways are still unclear. Through a number of assays, including cell viability, colony formation, and apotheosis assay, we found that AKR1B10 protected cells from UVC-induced DNA damage. Surprisingly, UVC-induced γH2AX foci and DNA double-strand breaks in the AKR1B10-overexpressing cells were ∼4-5 folds lower than those in the control group. The expression levels of AKR1B10, p53, chk1, chk2, nuclear factor (NF)-κB, and p65 showed dynamic changes in response to UVC irradiation. Our results suggested that AKR1B10 is involved in the pathway of cell cycle checkpoint and NF-κB in DNA damage. Taken together, our results suggest that AKR1B10 is involved in the repair of the DNA double-strand break, which provides a new insight into the role of AKR1B10 in DNA damage repair and indicates a new trail in tumorigenesis and cancer drug resistance.

Improved EGFR mutation detection sensitivity after enrichment by Cas9/sgRNA digestion and PCR amplification.

The detection of circulating tumor DNA is important in cancer research and clinical practice. In the present study, we aimed to improve the sensitivity of downstream mutation detection of next-generation sequencing using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system to selectively target wild-type fragments but with low or no cleavage activity to mutant fragments, followed by amplification using polymerase chain reaction. We selected different mutant sites of epidermal growth factor receptor gene (EGFR)-exon19 deletions in patients with lung cancer and constructed mixed templates of mutant and wild-type DNA comprising ratios of 10% to 0.01% to test the effectiveness of the enrichment method. The results showed that after CRISPR/Cas9 enrichment, a low concentration of mutant DNA fragments (0.01%) could be detected by Sanger sequencing, which represented a 1000-fold increase compared with the untreated samples. We further verified the feasibility of the introduced method and obtained similar results in clinical samples from patients with non-small cell lung cancer, indicating that this method has the potential to detect low copy number mutations at the early stage.

A novel long non-coding RNA-KAT7 is low expressed in colorectal cancer and acts as a tumor suppressor.

BACKGROUND: The abnormal expression of many long non-coding RNAs (lncRNAs) has been reported in the progression of various tumors. However, the potential biological roles and regulatory mechanisms of long non-coding RNAs in the development of colorectal cancer (CRC) have not yet been fully elucidated. Therefore, it is crucial to identify that lncRNAs can be used for the clinical prevention and treatment of CRC. METHODS: In our previous work, we identificated a novel lncRNA, lncRNA-KAT7, and found that the expression of lncRNA-KAT7 in CRC tissues was significantly lower than that in matched normal intestinal tissues, and the expression in CRC cell lines was lower than that of normal intestinal epithelial cells (P < 0.05). Besides, the expression of lncRNA-KAT7 is negative associated with age, tumor size, tumor differentiation, lymph node metastasis of CRC patients. The potential biological effects and molecular mechanisms of lncRNA-KAT7 in CRC were evaluated using a series of CCK-8 assay, clone formation assay, EdU proliferation assay, scratch determination, transwell determination, western blot analysis, and nude subcutaneous tumorigenesis model construction cell and animal experiments. RESULTS: The expression of lncRNA-KAT7 in CRC tissues was lower than that in matched normal tissues and normal intestinal epithelial cells (P < 0.05). Decreased expression of lncRNA-KAT7 is associated with clinicopathological features of poor CRC patients. In vitro experiments showed that up-regulation of lncRNA-KAT7 expression in CRC cells inhibited cell proliferation and migration. In vivo animal experiments showed that the lncRNA-KAT7 also inhibited tumor growth. Western blot analysis showed that the expression of lncRNA-KAT7 was up-regulated in HCT116 cells, the expression of E-cadherin increased, and the expression of Vimentin, MMP-2 and ß-catenin protein was down-regulated so did the phosphorylation NF-κB P65. The results confirm that the expression of lncRAN-KAT7 can inhibit the malignant phenotype of CRC cells. CONCLUSIONS: Up to now, as a novel lncRNA, lncRNA-KAT7 has not any relevant research and reports. The results confirm that the expression of lncRNA-KAT7 can inhibit the malignant phenotype of CRC cells. And it can be used as a new diagnostic biomarker and therapeutic target for the development of CRC.

A Novel Assay Coupling Dephosphorylation and Blue/White Colony Screening for the G > A Hotspot Mutation at Codon 13 of KRAS Gene.

Development of sensitive assay for detection of hotspot mutations of cancer driving gene is crucial for circulating tumor DNA analysis. This study tested the possibilities of applying restriction enzyme digestion and dephosphorylation coupled with blue/white screening technology for analyzing a hotspot point mutation in codon 13 of KRAS gene. The present study has documented that the combination of PCR with restriction digestion, dephosphorylation, blue/white screening and Sanger's sequencing can identify rare mutations with sensitivities at 0.003%. This novel assay with high sensitivity may have application in the diagnosis of early cancer targeting ctDNAs.

Heat shock protein 90-α mediates aldo-keto reductase 1B10 (AKR1B10) protein secretion through secretory lysosomes.

Aldo-keto reductase 1B10 (AKR1B10) protein is a new tumor biomarker in humans. Our previous studies have shown that AKR1B10 is secreted through a lysosome-mediated nonclassical pathway, leading to an increase in the serum of breast cancer patients. This study illuminates the regulatory mechanism of AKR1B10 secretion. The cytosolic AKR1B10 associates with and is translocated to lysosomes by heat shock protein 90α (HSP90α), a chaperone molecule. Ectopic expression of HSP90α significantly increased the secretion of endogenous AKR1B10 and exogenous GFP-AKR1B10 fusion protein when cotransfected. Geldanamycin, a HSP90α inhibitor, dissociated AKR1B10-HSP90α complexes and significantly reduced AKR1B10 secretion in a dose-dependent manner. We characterized the functional domain in AKR1B10 and found that helix 10 (amino acids 233-240), located at the C terminus, regulates AKR1B10 secretion. Targeted point mutations recognized that amino acids Lys-233, Glu-236, and Lys-240 in helix 10 mediate the interaction of AKR1B10 with HSP90α. Together, our data suggest that HSP90α mediates AKR1B10 secretion through binding to its helix 10 domain. This finding is significant in exploiting the use of AKR1B10 in cancer clinics.

Fiber Optic SPR POCT: A Novel Nucleic Acid Detection Biosensor for Environmental Viruses.

In the post-COVID-19 pandemic era, the long-term surveillance of pathogens is still important. The rapid detection of pathogens facilitates the accurate and convenient real-time monitoring of microbial contamination and improves the management of diseases. Here, a novel surface plasmon resonance (SPR)-based point of care testing (POCT) approach of microorganism nucleic acids with the guidance of CRISPR enzyme is described, including the application of optical fiber-based detection of trace SARS-CoV2 virus in sewage water on SPR and validation of the plasmonic biosensor for the detection of single-nucleotide mutations in natural water samples.

TRIM3 inhibits colorectal cancer cell migration and lipid droplet formation by promoting FABP4 degradation.

This study is to investigate the regulation of TRIM3/FABP4 on colorectal cancer (CRC) cell migration and lipid metabolism. After transfection of HCT116, LoVo, or SW480 cells, the expression of FABP4, TRIM3, N-cadherin, Vimentin, E-cadherin, and lipid droplet (LD) formation-related genes was measured by qRT-PCR or western blot assays. Wound healing and Transwell assays were applied to detect CRC cell migration and invasion abilities. The levels of triglyceride (TG) and total cholesterol (TC) were measured and the formation of LDs was observed. Additionally, the relationship between FABP4 and TRIM3 was confirmed by Co-IP and ubiquitination assays. Furthermore, a liver metastasis model of CRC was established to explore the effect of FABP4 on CRC tumor metastasis in vivo. FABP4 was upregulated in CRC cells. Downregulation of FABP4 or upregulation of TRIM3 resulted in repressed cell migration and invasion, decreased TG and TC levels, and reduced numbers of LDs. In nude mice, knockdown of FABP4 reduced metastatic nodules in the liver. Mechanistically, TRIM3 combined FABP4 and decreased its protein expression by ubiquitination. Overexpressed FABP4 reversed the influence of TRIM3 upregulation on CRC cell migration and LD formation. In conclusion, underexpressed TRIM3 suppressed FABP4 ubiquitination and accelerated CRC cell migration and LD formation.

Phosphoglycerate Kinase 1: An Effective Therapeutic Target in Cancer.

Phosphoglycerate kinase 1 (PGK1) serves as a pivotal enzyme in the cellular glycolysis pathway, facilitating adenosine-triphosphate (ATP) production in tumor cells and driving the Warburg effect. PGK1 generates ATP through the reversible phosphorylation reaction of 1,3-bisphosphoglycerate (1,3-BPG) to Mg-adenosine-5'-diphosphate (Mg-ADP). In addition to its role in regulating cellular metabolism, PGK1 plays a pivotal role in autophagy induction, regulation of the tricarboxylic acid cycle (TCA), and various mechanisms including tumor cell drug resistance, and so on. Given its multifaceted functions within cells, the involvement of PGK1 in many types of cancer, including breast cancer, astrocytoma, metastatic colon cancer, and pancreatic ductal adenocarcinoma, is intricate. Notably, PGK1 can function as an intracellular protein kinase to coordinate tumor growth, migration, and invasion via posttranslational modifications (PTMs). Furthermore, elevated expression levels of PGK1 have been observed in cancer tissues, indicating its association with unfavorable treatment outcomes and prognosis. This review provides a comprehensive summary of PGK1's expression pattern, structural features, functional properties, involvement in PTMs, and interaction with tumors. Additionally highlighted are the prospects for developing and applying related inhibitors that confirm the indispensable value of PGK1 in tumor progression.

Photo-metallo-immunotherapy: Fabricating Chromium-Based Nanocomposites to Enhance CAR-T Cell Infiltration and Cytotoxicity against Solid Tumors.

The infiltration and cytotoxicity of chimeric antigen receptor (CAR)-T cells are crucial for effective elimination of solid tumors. While metallo-immunotherapy is a promising strategy that can activate the antitumor immunity, its role in promoting CAR-T cell therapy remains elusive. The first single-element nanomaterial based on chromium nanoparticles (Cr NPs) for cancer photo-metallo-immunotherapy has been reported previously. Herein, an extended study using biodegradable polydopamine as a versatile carrier for these nanoparticles, enabling synergistic CAR-T cell therapy, is reported. The results show that these nanocomposites with or without further encapsulation of the anticancer drug alpelisib can promote the CAR-T cell migration and antitumor effect. Upon irradiation with near-infrared light, they caused mild hyperthermia that can "warm" the "cold" tumor microenvironment (TME). The administration of B7-H3 CAR-T cells to NOD severe combined immunodeficiency gamma mice bearing a human hepatoma or PIK3CA-mutated breast tumor can significantly inhibit the tumor growth after the induction of tumor hyperthermia by the nanocomposites and promote the secretion of serum cytokines, including IL-2, IFN-γ, and TNF-α. The trivalent Cr3+ ions, which are the major degradation product of these nanocomposites, can increase the CXCL13 and CCL3 chemokine expressions to generate tertiary lymphoid structures (TLSs) in the tumor tissues, facilitating the CAR-T cell infiltration.

CRISPR/Cas13a-based supersensitive circulating tumor DNA assay for detecting EGFR mutations in plasma.

Despite recent technological advancements in cell tumor DNA (ctDNA) mutation detection, challenges persist in identifying low-frequency mutations due to inadequate sensitivity and coverage of current procedures. Herein, we introduce a super-sensitivity and specificity technique for detecting ctDNA mutations, named HiCASE. The method utilizes PCR-based CRISPR, coupled with the restriction enzyme. In this work, HiCASE focuses on testing a series of EGFR mutations to provide enhanced detection technology for non-small cell lung cancer (NSCLC), enabling a detection sensitivity of 0.01% with 40 ng cell free DNA standard. When applied to a panel of 140 plasma samples from 120 NSCLC patients, HiCASE exhibits 88.1% clinical sensitivity and 100% specificity with 40 µL of plasma, higher than ddPCR and Super-ARMS assay. In addition, HiCASE can also clearly distinguish T790M/C797S mutations in different positions at a 1% variant allele frequency, offering valuable guidance for drug utilization. Indeed, the established HiCASE assay shows potential for clinical applications.

Epidermal growth factor induces tumour marker AKR1B10 expression through activator protein-1 signalling in hepatocellular carcinoma cells.

AKR1B10 (aldo-keto reductase 1B10) is overexpressed in liver and lung cancer, and plays a critical role in tumour development and progression through promoting lipogenesis and eliminating cytotoxic carbonyls. AKR1B10 is a secretory protein and potential tumour marker; however, little is known about the regulatory mechanism of AKR1B10 expression. The present study showed that AKR1B10 is induced by mitogen EGF (epidermal growth factor) and insulin through the AP-1 (activator protein-1) signalling pathway. In human HCC (hepatocellular carcinoma) cells (HepG2 and Hep3B), EGF (50 ng/ml) and insulin (10 nM) stimulated endogenous AKR1B10 expression and promoter activity. In the AKR1B10 promoter, a putative AP-1 element was found at bp -222 to -212. Deletion or mutation of this AP-1 element abrogated the basal promoter activity and response to EGF and AP-1 proteins. This AP-1 element bound to nuclear proteins extracted from HepG2 cells, and this binding was stimulated by EGF and insulin in a dose-dependent manner. Chromatin immunoprecipitation showed that the AP-1 proteins c-Fos and c-Jun were the predominant factors bound to the AP-1 consensus sequence, followed by JunD and then JunB. The same order was followed in the stimulation of endogenous AKR1B10 expression by AP-1 proteins. Furthermore, c-Fos shRNA (short hairpin RNA) and AP-1 inhibitors/antagonists (U0126 and Tanshinone IIA) inhibited endogenous AKR1B10 expression and promoter activity in HepG2 cells cultured in vitro or inoculated subcutaneously in nude mice. U0126 also inhibited AKR1B10 expression induced by EGF. Taken together, these results suggest that AKR1B10 is up-regulated by EGF and insulin through AP-1 mitogenic signalling and may be implicated in hepatocarcinogenesis.

Chemical genetics of acetyl-CoA carboxylases.

Chemical genetic studies on acetyl-CoA carboxylases (ACCs), rate-limiting enzymes in long chain fatty acid biosynthesis, have greatly advanced the understanding of their biochemistry and molecular biology and promoted the use of ACCs as targets for herbicides in agriculture and for development of drugs for diabetes, obesity and cancers. In mammals, ACCs have both biotin carboxylase (BC) and carboxyltransferase (CT) activity, catalyzing carboxylation of acetyl-CoA to malonyl-CoA. Several classes of small chemicals modulate ACC activity, including cellular metabolites, natural compounds, and chemically synthesized products. This article reviews chemical genetic studies of ACCs and the use of ACCs for targeted therapy of cancers.

Regulation of progesterone receptor expression in endometriosis, endometrial cancer, and breast cancer by estrogen, polymorphisms, transcription factors, epigenetic alterations, and ubiquitin-proteasome system.

The uterus and breasts are hormone-responsive tissues. Progesterone and estradiol regulate gonadotropin secretion, prepare the endometrium for implantation, maintain pregnancy, and regulate the differentiation of breast tissue. Dysregulation of these hormones causes endometriosis, endometrial cancer, and breast cancer, damaging the physical and mental health of women. Emerging evidence has shown that progesterone resistance or elevated progesterone activity is the primary hormonal substrate of these diseases. Since progesterone acts through its specific nuclear receptor, the abnormal expression of the progesterone receptor (PR) dysregulates progesterone function. This review discusses the regulatory mechanisms of PR expression in patients with endometriosis, and endometrial or breast cancer, including estrogen, polymorphisms, transcription factors, epigenetics, and the ubiquitin-proteasome system. (1) Estrogen promotes the expression of PRA (a PR isoform) mRNA and protein through the interaction of estrogen receptors (ERs) and Sp1 with half-ERE/Sp1 binding sites. ERs also affect the binding of Sp1 and Sp1 sites to promote the expression of PRB (another PR isoform)(2) PR polymorphisms, mainly PROGINS and + 331 G/A polymorphism, regulate PR expression by affecting DNA methylation and transcription factor binding. (3) The influence of epigenetic alterations on PR expression occurs through DNA methylation, histone modification, and microRNA. (4) As one of the main protein degradation pathways in vivo, the ubiquitin-proteasome system (UPS) regulates PR expression by participating in protein degradation. These mechanisms may provide new molecular targets for diagnosing and treating endometriosis, endometrial, and breast cancer.