Oncogenic Mutant p53 Sensitizes Non-Small Cell Lung Cancer Cells to Proteasome Inhibition via Oxidative Stress-Dependent Induction of Mitochondrial Apoptosis.

NSCLC is the leading cause of cancer death due, in part, to a lack of active therapies in advanced disease. We demonstrate that combination therapy with a proteasome inhibitor, BH3-mimetic, and chemotherapy is an active precision therapy in NSCLC cells and tumors expressing Onc-p53 alleles.

Low-density lipoprotein receptor-related protein 6 ablation in macrophages differentially inhibits lung injury-mediated inflammation and metastasis.

Low-density lipoprotein receptor-related protein 6 (LRP6) is a receptor protein for Wnt ligands. Yet, their role in immune cell regulation remains elusive. Here we demonstrated that genetic deletion of LRP6 in macrophages using LysM-cre Lrp6 (Lrp6) mice showed differential inhibition of inflammation in the bleomycin (BLM)-induced lung injury model and B16F10 melanoma lung metastasis model.

Coordinated phosphate uptake by extracellular alkaline phosphatase and solute carrier transporters in marine diatoms.

Marine diatoms express genes encoding potential phosphate transporter and alkaline phosphatase (APase) under phosphate-limited (-P) condition. This indicates that diatoms use high-affinity phosphate uptake system with organic phosphate hydration. The function of molecules playing roles for Pi uptake was determined in this study.

NOXA expression is downregulated in human breast cancer undergoing incomplete pathological response and senescence after neoadjuvant chemotherapy.

Neoadjuvant chemotherapy (NAC) is a frequently utilized approach to treat locally advanced breast cancer, but, unfortunately, a subset of tumors fails to undergo complete pathological response. Apoptosis and therapy-induced senescence (TIS) are both cell stress mechanisms but their exact role in mediating the pathological response to NAC is not fully elucidated. We investigated the change in expression of PAMIP1, the gene encoding for the pro-apoptotic protein, NOXA, following NAC in two breast cancer gene datasets, and the change in NOXA protein expression in response to NAC in 55 matched patient samples (pre- and post-NAC).

Targeting Oncogenic Mutant p53 and BCL-2 for Small Cell Lung Cancer Treatment.

Through a unique genomics and drug screening platform with ~800 solid tumor cell lines, we have found a subset of SCLC cell lines are hypersensitive to venetoclax, an FDA-approved inhibitor of BCL-2. SCLC-A (ASCL1 positive) and SCLC-P (POU2F3 positive), which make up almost 80% of SCLC, frequently express high levels of BCL-2. We found that a subset of SCLC-A and SCLC-P showed high BCL-2 expression but were venetoclax-resistant.

BRD4 Inhibition as a Strategy to Prolong the Response to Standard of Care in Estrogen Receptor-Positive Breast Cancer.

Breast cancer is the most commonly occurring malignancy in women and the second most common cause of cancer-related deaths. ER breast cancer constitutes approximately 70% of all breast cancer cases. The standard of care for ER breast cancer involves estrogen antagonists such as tamoxifen or fulvestrant in combination with CDK4/6 inhibitors such as palbociclib.

Pyrenoid-core CO2-evolving machinery is essential for diatom photosynthesis in elevated CO2.

Marine diatoms are responsible for up to 20% of the annual global primary production by performing photosynthesis in seawater where CO2 availability is limited while HCO3- is abundant. Our previous studies have demonstrated that solute carrier 4 proteins at the plasma membrane of the diatom Phaeodactylum tricornutum facilitate the use of the abundant seawater HCO3-. There has been an unconcluded debate as to whether such HCO3- use capacity may itself supply enough dissolved inorganic carbon (DIC) to saturate the enzyme Rubisco.

Pharmacologic Inhibition of SHP2 Blocks Both PI3K and MEK Signaling in Low-epiregulin HNSCC via GAB1.

Preclinical and clinical studies have evidenced that effective targeted therapy treatment against receptor tyrosine kinases (RTKs) in different solid tumor paradigms is predicated on simultaneous inhibition of both the PI3K and MEK intracellular signaling pathways. Indeed, re-activation of either pathway results in resistance to these therapies. Recently, oncogenic phosphatase SHP2 inhibitors have been developed with some now reaching clinical trials.

Targeting Stress-Response Pathways and Therapeutic Resistance in Head and Neck Cancer.

Head and neck cancer is the sixth leading cancer worldwide; head and neck squamous cell carcinoma (HNSCC) accounts for more than 90% of incident cases. In the US, cases of HNSCC associated with human papillomavirus (HPV) have been growing in proportion amongst a younger demographic with superior outcomes to the same treatments, relative to cases associated with tobacco. Yet failures to improve the long-term prognosis of advanced HNSCC over the last three decades persist in part due to intrinsic and acquired mechanisms of resistance.

Senolytic-Mediated Elimination of Head and Neck Tumor Cells Induced Into Senescence by Cisplatin.

Therapeutic outcomes achieved in head and neck squamous cell carcinoma (HNSCC) patients by concurrent cisplatin-based chemoradiotherapy initially reflect both tumor regression and tumor stasis. However, local and distant metastasis and disease relapse are common in HNSCC patients. In the current work, we demonstrate that cisplatin treatment induces senescence in both p53 wild-type HN30 and p53 mutant HN12 head and neck cancer models.

Androgen-deprivation induced senescence in prostate cancer cells is permissive for the development of castration-resistance but susceptible to senolytic therapy.

Prostate cancer (PCa) is one of the leading causes of cancer-related deaths in men. Although androgen deprivation therapies (ADT) and antiandrogens confer increased survival rates, most patients eventually develop castration resistant disease (CRPC). Previous studies have shown that these treatments have limited cytotoxicity, and instead, promote tumor cell growth arrest.

Construction of transgenic that exhibits new reddish leaf and flower colors due to introduction of β-carotene ketolase and hydroxylase genes.

, small white morning glory, is an ornamental plant belonging to the family Convolvulaceae, and cultivated worldwide. generates white petals including a pale-yellow colored star-shaped center (flower vein). Its fully opened flowers were known to accumulate trace amounts of carotenoids such as β-carotene.

Carboxylesterases for the hydrolysis of acetoacetate esters and their applications in terpenoid production using Escherichia coli.

Pathway engineering is a useful technology for producing desired compounds on a large scale by modifying the biosynthetic pathways of host organisms using genetic engineering. We focused on acetoacetate esters as novel low-cost substrates and established an efficient terpenoid production system using pathway-engineered recombinant Escherichia coli. Functional analysis using recombinant E.

Unmasking BCL-2 Addiction in Synovial Sarcoma by Overcoming Low NOXA.

Synovial sarcoma (SS) is frequently diagnosed in teenagers and young adults and continues to be treated with polychemotherapy with variable success. The SS18-SSX gene fusion is pathognomonic for the disease, and high expression of the anti-apoptotic BCL-2 pathologically supports the diagnosis. As the oncogenic SS18-SSX fusion gene itself is not druggable, BCL-2 inhibitor-based therapies are an appealing therapeutic opportunity.

FOSL1 promotes metastasis of head and neck squamous cell carcinoma through super-enhancer-driven transcription program.

Previously, we discovered that FOSL1 facilitates the metastasis of head and neck squamous cell carcinoma (HNSCC) cancer stem cells in a spontaneous mouse model. However, the molecular mechanisms remained unclear. Here, we demonstrated that FOSL1 serves as the dominant activating protein 1 (AP1) family member and is significantly upregulated in HNSCC tumor tissues and correlated with metastasis of HNSCC.

Pathway Engineering Using Escherichia coli to Produce Commercialized Carotenoids.

The biosynthesis of commercialized carotenoids (e.g., lycopene, β-carotene, zeaxanthin, and astaxanthin) using recombinant microorganisms is one of the reasonable and cost-effective alternatives to extraction from natural sources and chemical synthesis.

Clearance of therapy-induced senescent tumor cells by the senolytic ABT-263 via interference with BCL-X -BAX interaction.

Tumor cells undergo senescence in response to both conventional and targeted cancer therapies. The induction of senescence in response to cancer therapy can contribute to unfavorable patient outcomes, potentially including disease relapse. This possibiliy is supported by our findings that tumor cells induced into senescence by doxorubicin or etoposide can give rise to viable tumors in vivo.

Combination of fenretinide and ABT-263 induces apoptosis through NOXA for head and neck squamous cell carcinoma treatment.

The overall survival for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) remains low, with little progress made over decades. Cisplatin, most frequently used for HNSCC treatment, activates mitochondria-dependent apoptosis through the BCL-2 family proteins. We have previously demonstrated that the pro-apoptotic BH3-only protein, NOXA plays a critical role in this process.

Tumor cell escape from therapy-induced senescence.

H460 non-small cell lung, HCT116 colon and 4T1 breast tumor cell lines induced into senescence by exposure to either etoposide or doxorubicin were able to recover proliferative capacity both in mass culture and when enriched for the senescence-like phenotype by flow cytometry (based on β-galactosidase staining and cell size, and a senescence-associated reporter, BTG1-RFP). Recovery was further established using both real-time microscopy and High-Speed Live-Cell Interferometry (HSLCI) and was shown to be accompanied by the attenuation of the Senescence-Associated Secretory Phenotype (SASP). Cells enriched for the senescence-like phenotype were also capable of forming tumors when implanted in both immunodeficient and immunocompetent mice.

Mechanism of improving the rate of sono-oxidation of a KI solution by introduction of CO into an Ar atmosphere.

The rate of sono-oxidation of KI increased in a CO-Ar system compared to Ar alone. Higher values were obtained at 200 kHz with a maximum ratio of about forty. To determine the role of additional CO in the system, the effect of the pH of the reactant solution, the additional effect of NaHCO, sonoluminescence, and an analysis of products were examined.

Increased Synthesis of MCL-1 Protein Underlies Initial Survival of -Mutant Lung Cancer to EGFR Inhibitors and Provides a Novel Drug Target.

EGFR inhibitors (EGFRi) are effective against -mutant lung cancers. The efficacy of these drugs, however, is mitigated by the outgrowth of resistant cells, most often driven by a secondary acquired mutation in EGFR, We recently demonstrated that can arise during treatment; it follows that one potential therapeutic strategy to thwart resistance would be identifying and eliminating these cells [referred to as drug-tolerant cells (DTC)] prior to acquiring secondary mutations like We have developed DTCs to EGFRi in -mutant lung cancer cell lines. Subsequent analyses of DTCs included RNA-seq, high-content microscopy, and protein translational assays.