MARCH5 mediates NOXA-dependent MCL1 degradation driven by kinase inhibitors and integrated stress response activation

MCL1 has critical antiapoptotic functions and its levels are tightly regulated by ubiquitylation and degradation, but mechanisms that drive this degradation, particularly in solid tumors, remain to be established. We show here in prostate cancer cells that increased NOXA, mediated by kinase inhibitor activation of an integrated stress response, drives the degradation of MCL1, and identify the mitochondria-associated ubiquitin ligase MARCH5 as the primary mediator of this NOXA-dependent MCL1 degradation. Therapies that enhance MARCH5-mediated MCL1 degradation markedly enhance apoptosis in response to a BH3 mimetic agent targeting BCLXL, which may provide for a broadly effective therapy in solid tumors. Conversely, increased MCL1 in response to MARCH5 loss does not sensitize to BH3 mimetic drugs targeting MCL1, but instead also sensitizes to BCLXL inhibition, revealing a codependence between MARCH5 and MCL1 that may also be exploited in tumors withMARCH5 genomic loss.
Source: eLife - Category: Biomedical Science Tags: Cancer Biology Source Type: research

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Condition:   Prostate Carcinoma Interventions:   Procedure: Biospecimen Collection;   Other: Laboratory Biomarker Analysis;   Other: Quality-of-Life Assessment;   Other: Questionnaire Administration Sponsors:   University of Washington;   National Cancer Institute (NCI) Recruiting
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
Conditions:   Castration-Resistant Prostate Carcinoma;   Metastatic Prostate Adenocarcinoma;   Metastatic Prostate Small Cell Carcinoma;   Stage IV Prostate Cancer AJCC v8;   Stage IVA Prostate Cancer AJCC v8;   Stage IVB Prostate Cancer AJCC v8 Interventions:   Drug: BET Bromodomain Inhibitor ZEN-3694;   Drug: Enzalutamide;   Biological: Pembrolizumab Sponsors:   Rahul Aggarwal;   Zenith Epigenetics;   Merck&nb...
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
Could the administration of an yttrium-90-based radionuclide improve the performance...Read more on AuntMinnie.comRelated Reading: New PET/CT tracer reliably detects prostate cancer SABR slows prostate cancer progression PSMA-PET/CT again shows prowess for prostate cancer Choline-PET boosts mpMRI for prostate cancer detection
Source: AuntMinnie.com Headlines - Category: Radiology Source Type: news
(University of Gothenburg) In a new trial, Swedish researchers will investigate if a medicine normally used to treat prostate cancer can also be used to treat COVID-19 in patients. The desired effect is that the medicine will shorten the course of the disease and the need for intensive care. The drug itself is known to not least affect an enzyme important in prostate cancer cases and in corona infections.
Source: EurekAlert! - Medicine and Health - Category: International Medicine & Public Health Source Type: news
Contributors : Donald J Vander Griend ; Calvin VanOpstallSeries Type : Expression profiling by high throughput sequencingOrganism : Homo sapiensWe conducted RNA-sequencing to determine MEIS1-mediated gene regulation in prostate cancer cells because phenotypic data has demonstrated that expression of MEIS1 is sufficient to slow tumor growth and metastatic colonization in vitro and in vivo. These analyses compared global gene expression of CWR22Rv1-Control and CWR22Rv1-LV-MEIS1, as well as the HOXB13ko and HOXB13ko-LV-MEIS1 cells to precisely delineate MEIS1 and HOXB13-regulated genes. Importantly, inclusion of HOXB13ko line...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Homo sapiens Source Type: research
Publication date: Available online 13 July 2020Source: Pathology - Research and PracticeAuthor(s): Yu-Peng Wu, Zhi-Bin Ke, Fei Lin, Yao-An Wen, Sheng Chen, Xiao-Dong Li, Shao-Hao Chen, Xiong-Lin Sun, Jin-Bei Huang, Qing-Shui Zheng, Xue-Yi Xue, Yong Wei, Ning Xu
Source: Pathology Research and Practice - Category: Pathology Source Type: research
Could the administration of an yttrium-90-based radionuclide improve the performance...Read more on AuntMinnie.comRelated Reading: New PET/CT tracer reliably detects prostate cancer SABR slows prostate cancer progression PSMA-PET/CT again shows prowess for prostate cancer Choline-PET boosts mpMRI for prostate cancer detection
Source: AuntMinnie.com Headlines - Category: Radiology Source Type: news
In this study, we evaluated FASN expression at both mRNA and protein levels and assessed the association between FASN expression and prognosis in male Han Chinese with PCa treated with radical prostatectomy (RP). Methods: Expression profile and prognostic value of FASN were analyzed in tissue microarray (TMA) and data retrieved from databases including TCGA public database, GEO database, and our sequencing data with whole clinicopathological characteristics. Results: FASN expression was associated with clinical parameters and biochemical recurrence of prostate cancer. The relative expression of FASN mRNA was higher...
Source: Disease Markers - Category: Laboratory Medicine Tags: Dis Markers Source Type: research
Frequencies of genomic alterations in current therapeutic targets similar for AFR, EUR men
Source: The Doctors Lounge - Oncology - Category: Cancer & Oncology Tags: Oncology, Pathology, Pharmacy, Urology, Journal, Source Type: news
We examined the underlying mechanisms using cell lines and tumour tissue samples. IGF-I had differential effects on the process of EMT: inhibiting in normal and promoting in cancer cells, whereas hyperglycamia alone had a stimulatory effect in both. These effects were independent of IGF and in both cases, hyperglycaemia induced an increase IGFBP-2(tumour promoter) and FOXA1. A positive correlation existed between levels of IGFBP-2 and FOXA1 in benign and cancerous prostate tissue samples and in vitro and in vivo data indicated that FOXA1 strongly interacted with the IGFBP-2 gene in normal prostate epithelial cells that was...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research
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