Unveiling the dark side of glucose-regulated protein 78 (GRP78) in cancers and other human pathology: a systematic review.

Glucose-Regulated Protein 78 (GRP78) is a chaperone protein that is predominantly expressed in the lumen of the endoplasmic reticulum. GRP78 plays a crucial role in protein folding by assisting in the assembly of misfolded proteins. Under cellular stress conditions, GRP78 can translocate to the cell surface (csGRP78) were it interacts with different ligands to initiate various intracellular pathways. The expression of csGRP78 has been associated with tumor initiation and progression of multiple cancer types. This review provides a comprehensive analysis of the existing evidence on the roles of GRP78 in various types of cancer and other human pathology. Additionally, the review discusses the current understanding of the mechanisms underlying GRP78's involvement in tumorigenesis and cancer advancement. Furthermore, we highlight recent innovative approaches employed in downregulating GRP78 expression in cancers as a potential therapeutic target.

Co-Targeting Nucleus Accumbens Associate 1 and NF-κB Signaling Synergistically Inhibits Melanoma Growth.

Nucleus-accumbens-associated protein-1 (NAC1) is a cancer-related transcriptional factor encoded by the NACC1 gene, which is amplified and overexpressed in various human cancers and has been appreciated as one of the top potential cancer driver genes. NAC1 has therefore been explored as a potential therapeutic target for managing malignant tumors. Here, we show that NAC1 is a negative regulator of NF-κB signaling, and NAC1 depletion enhances the level of the nuclear NF-κB in human melanoma. Furthermore, the inhibition of NF-κB signaling significantly potentiates the antineoplastic activity of the NAC1 inhibition in both the cultured melanoma cells and xenograft tumors. This study identifies a novel NAC1-NF-κB signaling axis in melanoma, offering a promising new therapeutic option to treat melanoma.

Identification of a NACC1-Regulated Gene Signature Implicated in the Features of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC), characterized by a deficiency in estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor2 (HER2), is among the most lethal subtypes of breast cancer (BC). Nevertheless, the molecular determinants that contribute to its malignant phenotypes such as tumor heterogeneity and therapy resistance, remain elusive. In this study, we sought to identify the stemness-associated genes involved in TNBC progression. Using bioinformatics approaches, we found 55 up- and 9 downregulated genes in TNBC. Out of the 55 upregulated genes, a 5 gene-signature (CDK1, EZH2, CCNB1, CCNA2, and AURKA) involved in cell regeneration was positively correlated with the status of tumor hypoxia and clustered with stemness-associated genes, as recognized by Parametric Gene Set Enrichment Analysis (PGSEA). Enhanced infiltration of immunosuppressive cells was also positively correlated with the expression of these five genes. Moreover, our experiments showed that depletion of the transcriptional co-factor nucleus accumbens-associated protein 1 (NAC1), which is highly expressed in TNBC, reduced the expression of these genes. Thus, the five genes signature identified by this study warrants further exploration as a potential new biomarker of TNBC heterogeneity/stemness characterized by high hypoxia, stemness enrichment, and immune-suppressive tumor microenvironment.

GSTM2 is a key molecular determinant of resistance to SG-ARIs.

Prostate cancer (PCa) continues to threaten men's health, and treatment targeting the androgen receptor (AR) pathway is the major therapy for PCa patients. Several second-generation androgen receptor inhibitors (SG-ARIs), including enzalutamide (ENZ), apalutamide (APA) and darolutamide (DARO), have been developed to better block the activity of AR. Unavoidably, emergence of resistance to these novel drugs still persists. Herein, we identified glutathione S-transferase Mu 2 (GSTM2) as an important determinant in the acquisition of resistance to SG-ARIs. Elevated GSTM2 was detected in enzalutamide-resistant (ENZ-R) PCa, and overexpression of GSTM2 in naïve enzalutamide-sensitive (ENZ-S) cells effectively transformed them to ENZ-R PCa. Aryl hydrocarbon receptor (AhR), the upstream transcription factor, was implicated in the overexpression of GSTM2 in ENZ-R cells. Mechanistically, GSTM2 antagonized the effect of ENZ by rescuing cells from oxidative stress-associated damage and activation of p38 MAPK pathway. Surprisingly, high GSTM2 levels also associated with cross-resistance to APA and DARO. Taking together, these results provide new insight to ameliorate resistance to SG-ARIs and improve treatment outcome.

Removal of lead ions from water using thiophene-functionalized metal-organic frameworks.

Heavy metal ion contamination in water is a hazard to all life. The removal of such ions from aqueous media by porous metal-organic frameworks (MOFs) is a growing field. Herein we report the use of thiophene containing MOFs, notably DUT-67, for the removal of Pb2+ ions from water under both batch and flow conditions with a max loading of 98.5 mg Pb2+ per g MOF. Solution-phase 207Pb NMR spectroscopy and an observed decrease in adsorption with non-thiophene containing systems support a mechanism of adsorption via a putative 6π-η5-thiophene-Pb2+ coordination.

Phytochemical Screening and Synergistic Anti-proliferative Activity against Selected Cancer Cell Lines of Moringa oleifera and Indigofera arrecta Leaf Extracts

Medicinal plants present a plausible source for anticancer agents. Combination of plant extracts and plant-derived compounds with the currently used cancer drugs has shown a marked improvement of the conventional drugs' efficacy and reduced toxicity. This study evaluated; phytochemical screening, antiproliferative activity and drug interaction potentials of Moringa oleifera and Indigofera arrecta leaf extracts with 5-fluoro uracil against selected cancer cell lines. Phytochemical screening was done using standard procedures. The common 3– (4, 5-dimethylthiazol-2-yr) -2, 5-diphenyltetrazolium (MTT) assay was used to determine the growth inhibitory potential of the extracts towards cancer cells. Drug interaction assays were done using constant ratio combination method. Alkaloids, terpenoids, tannins, flavonoids, glycosides, phenols and saponins were found to be present in the plant's extracts. M. oleifera and I. arrecta methanol-dichloromethane extracts had the highest activity compared to water extracts. All the extracts showed antiproliferative activities towards; HCC 1395 (breast), DU145 (prostate) and Hela (cervical) cancer cell lines. The extracts were not cytotoxic towards Vero cells (IC50>1000 µg/ml). I. arrecta and M. oleifera inhibited DU145 the most with IC50 values of 111.110 µg/ml and 66.290 µg/ml respectively. The plant extracts synergistically inhibited the growth of cancer cells (CI<1). Combination of the plant extracts and 5-Fluorouracil depicted that the concentration of the conventional drug could be reduced and yet achieve the same desired effect against cancerous cells (Dose reduction index (DRI) >1). Further studies to isolate the bioactive compounds and deduce the probable mechanisms of action are recommended.