Ferroptosis is a type of programmed cell death induced by the accumulation of lipid peroxidation and lipid reactive oxygen species in cells. It has been recently demonstrated that cancer cells are ...vulnerable to ferroptosis inducers (FIN). However, the therapeutic potential of FINs in prostate cancer in preclinical settings has not been explored. In this study, we demonstrate that mediators of ferroptosis, solute carrier family 7 member 11, SLC3A2, and glutathione peroxidase, are expressed in treatment-resistant prostate cancer. We further demonstrate that treatment-resistant prostate cancer cells are sensitive to two FINs, erastin and RSL3. Treatment with erastin and RSL3 led to a significant decrease in prostate cancer cell growth and migration
and significantly delayed the tumor growth of treatment-resistant prostate cancer
, with no measurable side effects. Combination of erastin or RSL3 with standard-of-care second-generation antiandrogens for advanced prostate cancer halted prostate cancer cell growth and migration
and tumor growth
. These results demonstrate the potential of erastin or RSL3 independently and in combination with standard-of-care second-generation antiandrogens as novel therapeutic strategies for advanced prostate cancer. SIGNIFICANCE: These findings reveal that induction of ferroptosis is a new therapeutic strategy for advanced prostate cancer as a monotherapy and in combination with second-generation antiandrogens.
Mitochondrial transport along microtubules is mediated by Miro1 and TRAK adaptors that recruit kinesin-1 and dynein-dynactin. To understand how these opposing motors are regulated during ...mitochondrial transport, we reconstitute the bidirectional transport of Miro1/TRAK along microtubules in vitro. We show that the coiled-coil domain of TRAK activates dynein-dynactin and enhances the motility of kinesin-1 activated by its cofactor MAP7. We find that TRAK adaptors that recruit both motors move towards kinesin-1's direction, whereas kinesin-1 is excluded from binding TRAK transported by dynein-dynactin, avoiding motor tug-of-war. We also test the predictions of the models that explain how mitochondrial transport stalls in regions with elevated Ca
. Transport of Miro1/TRAK by kinesin-1 is not affected by Ca
. Instead, we demonstrate that the microtubule docking protein syntaphilin induces resistive forces that stall kinesin-1 and dynein-driven motility. Our results suggest that mitochondrial transport stalls by Ca
-mediated recruitment of syntaphilin to the mitochondrial membrane, not by disruption of the transport machinery.
Abstract Tanacetum parthenium (L.) Schultz-Bip (feverfew) is among the important medicinal and aromatic plants due to its tryptophan (TRP), serotonin (SER), melatonin (MEL), and parthenolide (PRT) ...content. In recent studies, have reported TRP, MEL, and (PRT) are effective in the treatment of COVID-19, thus increasing the popularity of feverfew, which is rich in these valuable molecules. This study investigated the possible effects of exogenous foliar applications of methyl jasmonate (MeJA 0.5 mM) and TRP (20 mM) on plant TRP, SER, MEL, and PRT levels. During the pre-flowering period, endogenous TRP was measured as 128.9 µg/mL and endogenous PRT as 1.53% mg/g in the leaves of the control group. During the flowering period, the MEL level was measured as 1.38 µg/mL in the leaves of the TRP application group. In addition, in the pre-flowering period, MeJA-induced increases of 94.51% were determined in DPPH antioxidant activity and the total flavonoid content was 38.76 mg QE/g, whereas the highest total phenolic content of 51.63 mg GAE/g was found in flower samples of the control group. However, neither the developmental periods nor the treatments significantly affected the total phenolic content in the leaves.
Abstract
Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer that rarely develops de novo in primary tumors and is commonly acquired during the development of treatment ...resistance. NEPC is characterized by gain of neuroendocrine markers and loss of androgen receptor (AR), making it resistant to current therapeutic strategies targeting the AR signaling axis. Here, we report that MCM2, MCM3, MCM4, and MCM6 (MCM2/3/4/6) are elevated in human NEPC and high levels of MCM2/3/4/6 are associated with liver metastasis and poor survival in prostate cancer patients. MCM2/3/4/6 are four out of six proteins that form a core DNA helicase (MCM2-7) responsible for unwinding DNA forks during DNA replication. Inhibition of MCM2-7 by treatment with ciprofloxacin inhibits NEPC cell proliferation and migration in vitro, significantly delays NEPC tumor xenograft growth, and partially reverses the neuroendocrine phenotype in vivo. Our study reveals the clinical relevance of MCM2/3/4/6 proteins in NEPC and suggests that inhibition of MCM2-7 may represent a new therapeutic strategy for NEPC.
Prostate cancer remains the most common non-cutaneous malignancy among men in the United States. To discover potential serum-based biomarkers for high-risk prostate cancer, we performed a ...high-multiplex immunoassay utilizing patient-matched pre-operative and post-operative serum samples from ten men with high-grade and high-volume prostate cancer. Our study identified six (CASP8, MSLN, FGFBP1, ICOSLG, TIE2 and S100A4) out of 174 proteins that were significantly decreased after radical prostatectomy. High levels of CASP8 were detected in pre-operative serum samples when compared to post-operative serum samples and serum samples from patients with benign prostate hyperplasia (BPH). By immunohistochemistry, CASP8 protein was expressed at higher levels in prostate cancer tissues compared to non-cancerous and BPH tissues. Likewise, CASP8 mRNA expression was significantly upregulated in prostate cancer when compared to benign prostate tissues in four independent clinical datasets. In addition, mRNA levels of CASP8 were higher in patients with recurrent prostate cancer when compared to patients with non-recurrent prostate cancer and high expression of CASP8 was associated with worse disease-free survival and overall survival in renal cancer. Together, our results suggest that CASP8 may potentially serve as a biomarker for high-risk prostate cancer and possibly renal cancer.
Prostate cancer is responsible for over 30,000 US deaths annually, attributed largely to incurable metastatic disease. Here, we demonstrate that high levels of plectin are associated with localized ...and metastatic human prostate cancer when compared to benign prostate tissues. Knock-down of plectin inhibits prostate cancer cell growth and colony formation in vitro, and growth of prostate cancer xenografts in vivo. Plectin knock-down further impairs aggressive and invasive cellular behavior assessed by migration, invasion, and wound healing in vitro. Consistently, plectin knock-down cells have impaired metastatic colonization to distant sites including liver, lung, kidney, bone, and genitourinary system. Plectin knock-down inhibited number of metastases per organ, as well as decreased overall metastatic burden. To gain insights into the role of plectin in prostate cancer growth and metastasis, we performed proteomic analysis of prostate cancer plectin knock-down xenograft tissues. Gene set enrichment analysis shows an increase in levels of proteins involved with extracellular matrix and laminin interactions, and a decrease in levels of proteins regulating amino acid metabolism, cytoskeletal proteins, and cellular response to stress. Collectively these findings demonstrate that plectin is an important regulator of prostate cancer cell growth and metastasis.
Distinguishing clinically significant from indolent prostate cancer (PC) is a major clinical challenge. We utilised targeted protein biomarker discovery approach to identify biomarkers specific for ...pro-metastatic PC. Serum samples from the cancer-free group; Cambridge Prognostic Group 1 (CPG1, low risk); CPG5 (high risk) and metastatic disease were analysed using Olink Proteomics panels. Tissue validation was performed by immunohistochemistry in a radical prostatectomy cohort (n = 234). We discovered that nine proteins (pleiotrophin (PTN), MK, PVRL4, EPHA2, TFPI-2, hK11, SYND1, ANGPT2, and hK14) were elevated in metastatic PC patients when compared to other groups. PTN levels were increased in serum from men with CPG5 compared to benign and CPG1. High tissue PTN level was an independent predictor of biochemical recurrence and metastatic progression in low- and intermediate-grade disease. These findings suggest that PTN may represent a novel biomarker for the presence of poor prognosis local disease with the potential to metastasise warranting further investigation.
Breast cancer remains the second most lethal cancer among women in the United States and triple-negative breast cancer is the most aggressive subtype with limited treatment options. Trop2, a cell ...membrane glycoprotein, is overexpressed in almost all epithelial cancers. In this study, we demonstrate that Trop2 is overexpressed in triple-negative breast cancer (TNBC), and downregulation of Trop2 delays TNBC cell and tumor growth supporting the oncogenic role of Trop2 in breast cancer. Through proteomic profiling, we discovered a metabolic signature comprised of TALDO1, GPI, LDHA, SHMT2, and ADK proteins that were downregulated in Trop2-depleted breast cancer tumors. The identified oncogene-mediated metabolic gene signature is significantly upregulated in TNBC patients across multiple RNA-expression clinical datasets. Our study further reveals that the metabolic gene signature reliably predicts poor survival of breast cancer patients with early stages of the disease. Taken together, our study identified a new five-gene metabolic signature as an accurate predictor of breast cancer outcome.
Son yıllarda bitkisel kaynaklı antioksidan ve antimikrobiyal maddelere olan ilginin artmasıyla birlikte uçucu yağlar üzerinde yapılan bilimsel çalışmalar literatürde daha çok yer almaya başlamıştır. ...Bu çalışmada, Balıkesir yöresinden toplanan biberiye (Rosmarinus officinalis L) ve fesleğen (Ocimum basilicum L.) bitkilerine ait uçucu yağların antioksidan ve antimikotik özellikleri incelenmiştir. Bitkilerden hidrodistilasyon yöntemiyle elde edilen uçucu yağların antimikotik etkileri sırasıyla küf ve maya örnekleri olarak seçilen Aspergillus parasiticus (DSM 5771) ve Zygosaccharomyces rouxii (ATCC 28253) üzerinde in vitro olarak araştırılmıştır. Uçucu yağların antioksidan özelliklerini belirlemek amacıyla toplam fenolik madde analizi ve toplam antioksidan yakalama kapasitesi tayini yapılmıştır. Çalışma kapsamında elde edilen sonuçların endüstriyel olarak üretimi ve son tüketiciye satışı yapılan örneklerle kıyaslanması için uçucu yağların, ticari muadilleri de antimikotik ve antioksidan özellikler açısından incelenmiştir. Araştırma bulguları Balıkesir yöresinden toplanan biberiye ve fesleğen bitkilerinin değişen oranlarda antimikotik ve antioksidan özellikte olduğunu göstermiştir. Çalışma sonuçları, farklı lokasyonlardan toplanan bitkilerin antimikotik ve antioksidan özellikleri arasında istatistiki olarak önemli (P
Türkiye’de mobilya sektörü, firma sayısı, mobilya üretim kapasiteleri, tüketici talepleri ve son dönemlerde hızlı artan ihracat talepleri göz önüne alındığında, ülke ekonomisinde önemli bir yer ...tutmaktadır. Mobilya açısından, tüketici tercihini etkileyen kriterlerin tespit edilmesi, sektör için önemli bir konudur. Bu çalışmada mobilya alanında uzmanlara (akademisyen, mimar ve mühendis vb.) ve sektör dışında bulunan kullanıcılara anket yapılmıştır. Mobilya tercihlerini etkileyen kriterler, ana ve alt kriterler halinde belirlenmiştir. Anketlerde, Likert ölçeğinden yararlanılarak, bu kriterlerin önem derecesine göre puanlanması talep edilmiştir. Anket verilerinden elde edilen puanlara göre her kriterin ortalaması alınarak, ana ve alt kriterlerin ortalama puan değerleri hesaplanmıştır. Anket sonuçlarına göre, mobilya tercihinde etkili olan kriterlere bakıldığında, sektörde yer alan uzmanlar ile kullanıcılar arasında öncelikli kriterler açısından farklılıklar görülmüştür. Mobilya tasarım ve üretim süreçlerinde yer alan uzmanların, kullanıcı beklentilerini göz önünde bulundurması oldukça önem taşımaktadır. Mobilya sektörü, değişimlerin yaşandığı pazar ortamında rekabet gücünü sağlayabilmek için, ürün geliştirirken kullanıcı beklentilerini ve hedef pazarda etkili olan kriterleri dikkate almalıdır. Mobilya firmalarının başarısında, mobilyanın kullanım alanı ve kullanıcı açısından beklentilerinin doğru bir şekilde analiz edilmesi etkili olmaktadır.
The furniture sector in Turkey is important for the country’s economy, considering the number of companies, furniture production capacities, consumer demands and the rapidly increasing export demands in recent times. In terms of furniture, determining the criteria that affect consumer choice is an important issue for the sector. In this study, surveys were conducted with experts in the field of furniture (academicians, architects, engineers, etc.) and users outside the sector. The criteria affecting the furniture preferences are determined as main and sub-criteria. By using the Likert scale in the surveys, it was requested that these criteria be scored according to the degree of importance. The average score values of the main and sub-criteria were calculated by taking the average of each criterion according to the scores obtained from the survey data. According to the results of the survey, when the criteria that are effective in choosing furniture are examined, there are differences between the experts in the sector and the users in terms of priority criteria. It is very important for experts involved in furniture design and production processes to consider user expectations. The furniture industry should consider the user expectations and the criteria that are effective in the target market while developing the product, in order to ensure its competitiveness in the market environment where changes are experienced. The correct analysis of the furniture’s usage area and expectations of the user is effective in the success of furniture companies.
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