MTOR signaling orchestrates stress-induced mutagenesis, facilitating adaptive evolution in cancer

Science ◽  
2020 ◽  
Vol 368 (6495) ◽  
pp. 1127-1131 ◽  
Author(s):  
Arcadi Cipponi ◽  
David L. Goode ◽  
Justin Bedo ◽  
Mark J. McCabe ◽  
Marina Pajic ◽  
...  
Keyword(s):  
Human Cancer ◽  
Rapid Expansion ◽  
Multiple Cancer ◽  
Two Phase ◽  
In Vivo Models ◽  
A Genome ◽  
Induced Mutagenesis ◽  
Stress Sensing

In microorganisms, evolutionarily conserved mechanisms facilitate adaptation to harsh conditions through stress-induced mutagenesis (SIM). Analogous processes may underpin progression and therapeutic failure in human cancer. We describe SIM in multiple in vitro and in vivo models of human cancers under nongenotoxic drug selection, paradoxically enhancing adaptation at a competing intrinsic fitness cost. A genome-wide approach identified the mechanistic target of rapamycin (MTOR) as a stress-sensing rheostat mediating SIM across multiple cancer types and conditions. These observations are consistent with a two-phase model for drug resistance, in which an initially rapid expansion of genetic diversity is counterbalanced by an intrinsic fitness penalty, subsequently normalizing to complete adaptation under the new conditions. This model suggests synthetic lethal strategies to minimize resistance to anticancer therapy.

scholarly journals In-silico investigation of curcumin drug-likeness, gene-targets and prognostic relevance of the targets in panels of human cancer cohorts

2021 ◽  
Vol 14 (1) ◽  
pp. 037-046
Author(s):  
David B Oshevire ◽  
Aishatu Mustapha ◽  
Blessing U. Alozieuwa ◽  
Hassana H. Badeggi ◽  
Abdulfatai Ismail ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Human Cancer ◽  
Treatment Modalities ◽  
Drug Candidate ◽  
Anticancer Activities ◽  
Multiple Cancer ◽  
In Vivo Models ◽  
Lipinski’S Rule

Despite advancements in diagnostic and standard treatment modalities, cancer survival rate remains disappointing globally. It has however, been recognized that exploring the therapeutic properties of secondary metabolite from natural products may alleviate the problems of drug resistance and toxicity that besiege the conventional therapies, and hence improve the overall prognosis of cancer patient. To this end curcumin, a polyphenolic natural compound has been widely studied for it anticancer activities in in vitro and in vivo models. Computational technology has significantly improved the success rate of drug discovery and development, hence, it has become a widely explore tool in drug candidate identification. In this study we used computational approached to identify 12 genes that are potential druggable candidate for curcumin. The genes identified were found to be enriched in cancer and drug resistance associated signaling pathways. Interestingly, the top 3 identified genes; Microtubule-associated protein tau (MAPT), Toll-like receptor 9 (TLR9) and Tyrosyl-DNA phosphodiesterase 1 (TDP1) were observed to be over expressed in multiple cancer cohorts and were associated with poor prognoses of the patients. Curcumin has good physicochemical, bioavailability and ADMET properties. Importantly, it met the Lipinski's Rule of 5 for drug likeness and thus worthy of further in vitro and in vivo confirmation studies.

scholarly journals FAM64A Promotes Prostate Cancer Growth In Vivo and In Vitro

2020 ◽  
Author(s):  
Feilun Cui ◽  
Zhipeng Xu ◽  
Yumei Lv ◽  
Jianpeng Hu
Keyword(s):  
Prostate Cancer ◽  
Molecular Mechanisms ◽  
Human Cancer ◽  
Bioinformatic Analysis ◽  
In Vitro Assays ◽  
Multiple Cancer ◽  
Cell Matrix ◽  
Public Datasets

Abstract Background Prostate cancer (PCa) is the most common type of human cancer in males. However, the mechanisms underlying PCa tumorigenesis remained unclear.Methods The present study evaluated the expression levels of FAM64A in PCa by using 5 public datasets, including GSE8511, GSE45016, GSE55945, GSE38241 and GSE17951. Then, in vivo and in vitro assays were conducted to detect the biological functions of FAM64A in PCa. Microarray and bioinformatic analysis were carried out to detect the downstream targets and pathways regulated by FAM64A.Results In this study, we for first time demonstrate FAM64A as a biomarker for PCa. FAM64A was found to be overexpressed in PCa compared to normal samples. Higher FAM64A expression were found in Gleason score (GS) ≥ 8 PCa compared to GS < 8 PCa samples, in N1 staging compared to N1 staging PCa samples, and T3/4 staging compared to T1 staging PCa. Moreover, higher FAM64A expression was correlated to shorter survival time in PCa. Knockdown of FAM64A significantly suppressed PCa cell proliferation and colony formation, however, induced PCa apoptosis in vivo and in vitro. Bioinformatics analysis combined with microarray analysis revealed FAM64A played crucial roles in regulating multiple cancer related pathways, including cell-matrix adhesion and cAMP signaling pathway. Conclusions These results showed FAM64A could serve as a novel biomarker for PCa and will be helpful to understand the underlying FAM64A -related molecular mechanisms in the progression of PCa.

Toxicity study of ochratoxin A using HEK293 and HepG2 cell lines based on microRNA profiling

2016 ◽  
Vol 36 (1) ◽  
pp. 8-22 ◽  
Author(s):  
J Zhao ◽  
X Qi ◽  
Q Dai ◽  
X He ◽  
H Dweep ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Ochratoxin A ◽  
Cell Lines ◽  
Human Cancer ◽  
Hek293 Cells ◽  
Signal Transduction Pathways ◽  
In Vivo Models ◽  
Mammalian Cell Lines

Ochratoxin A (OTA) induced DNA damage, cytotoxicity, and apoptosis in mammalian cell lines. Micro RNAs (miRNAs) are involved in physiological and developmental processes and contribute to cancer development and progression. In our study, high-throughput miRNA profiling and Kyoto Encyclopedia of Genes and Genomes analysis were applied to comparatively study the toxicity of OTA in HEK293 cells and HepG2 cells treated with 25 μM OTA for 24 h. In these two cells, the same changing miRNAs were mostly related to signal transduction pathways, whereas the different changing miRNAs were mostly related to human cancer pathways. DGCR8, Dicer1, and Drosha were significantly suppressed in HEK293 cells, indicating an impairment of miRNA biogenesis. The damage seemed more extensive in HEK293 cells. Cell models and in vivo models were also compared. Many miRNAs in vitro were markedly different from those in vivo; however, OTA toxicity was observed both in vitro and in vivo. The classification of deregulated pathways is similar. The biogenesis of miRNA was impaired in both lines. In conclusion, deregulated miRNAs in vitro are mostly related to human cancer and signal transduction pathways. The deregulated pathways in vivo are similar to those in vitro.

scholarly journals Evaluation of the Efficacy & Biochemical Mechanism of Cell Death Induction by Piper longum Extract Selectively in In-Vitro and In-Vivo Models of Human Cancer Cells

PLoS ONE ◽  
2014 ◽  
Vol 9 (11) ◽  
pp. e113250 ◽  
Author(s):  
Pamela Ovadje ◽  
Dennis Ma ◽  
Phillip Tremblay ◽  
Alessia Roma ◽  
Matthew Steckle ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Human Cancer ◽  
Biochemical Mechanism ◽  
In Vivo Models ◽  
Piper Longum ◽  
Human Cancer Cells

scholarly journals Dose-Dependent Internalization and Externalization Integrity Study of Newly Synthesized 99mTc-Thymoquinone Radiopharmaceutical as Cancer Theranostic Agent

Dose-Response ◽  
2020 ◽  
Vol 18 (2) ◽  
pp. 155932582091418
Author(s):  
Saima Tariq ◽  
Syed Ali Raza Naqvi ◽  
Sumaira Naz ◽  
Muhammad Samee Mubarik ◽  
Muhammad Yaseen ◽  
...  
Keyword(s):  
Blood Serum ◽  
Nigella Sativa ◽  
Biological Activities ◽  
Phase I Clinical Trials ◽  
Anticancer Activities ◽  
Multiple Cancer ◽  
In Vivo Models ◽  
Theranostic Agent

Thymoquinone (TQ) is a bioactive phytochemical isolated from Nigella sativa and has been investigated for biochemical and biological activities in both in vitro and in vivo models. It is best known for its anticancer activities. Thymoquinone accomplishes anticancer activities through targeting multiple cancer markers including PPAR-γ, PTEN, P53, P73, STAT3, and generation of reactive oxygen species at the cancer cell surface. The radiolabeling of TQ with γ- and β-emitter radionuclide could be used as cancer diagnostic or therapeutic radiopharmaceutical, respectively. In this study, we are reporting the radiolabeling of TQ with technetium-99m (99mTc), stability in saline and blood serum, internalization and externalization of 99mTc-TQ using rhabdomyosarcoma cancer cells line. The quality control study revealed more than 95% labeling yield and stable in blood serum up to 4 hours. In vitro internalization rate was recorded 27.08% ± 0.95% at 1 hour post 2 hours internalization period and comparatively slow externalization. The results of this study are quite encourging and could be investigated for further key preclinical parameters to enter phase I clinical trials.

scholarly journals Cancer-associated mutations reveal a novel role for EpCAM as an inhibitor of cathepsin-L and tumor cell invasion

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Narendra V. Sankpal ◽  
Taylor C. Brown ◽  
Timothy P. Fleming ◽  
John M. Herndon ◽  
Anusha A. Amaravati ◽  
...  
Keyword(s):  
Cell Surface ◽  
Tumor Cell ◽  
Cell Invasion ◽  
Human Cancer ◽  
Cathepsin L ◽  
Surface Expression ◽  
Tumor Cell Invasion ◽  
In Vivo Models

Abstract Background EpCAM (Epithelial cell adhesion molecule) is often dysregulated in epithelial cancers. Prior studies implicate EpCAM in the regulation of oncogenic signaling pathways and epithelial-to-mesenchymal transition. It was recently demonstrated that EpCAM contains a thyroglobulin type-1 (TY-1) domain. Multiple proteins with TY-1 domains are known to inhibit cathepsin-L (CTSL), a cysteine protease that promotes tumor cell invasion and metastasis. Analysis of human cancer sequencing studies reveals that somatic EpCAM mutations are present in up to 5.1% of tested tumors. Methods The Catalogue of Somatic Mutations in Cancer (COSMIC) database was queried to tabulate the position and amino acid changes of cancer associated EpCAM mutations. To determine how EpCAM mutations affect cancer biology we studied C66Y, a damaging TY-1 domain mutation identified in liver cancer, as well as 13 other cancer-associated EpCAM mutations. In vitro and in vivo models were used to determine the effect of wild type (WT) and mutant EpCAM on CTSL activity and invasion. Immunoprecipitation and localization studies tested EpCAM and CTSL protein binding and determined compartmental expression patterns of EpCAM mutants. Results We demonstrate that WT EpCAM, but not C66Y EpCAM, inhibits CTSL activity in vitro, and the TY-1 domain of EpCAM is responsible for this inhibition. WT EpCAM, but not C66Y EpCAM, inhibits tumor cell invasion in vitro and lung metastases in vivo. In an extended panel of human cancer cell lines, EpCAM expression is inversely correlated with CTSL activity. Previous studies have demonstrated that EpCAM germline mutations can prevent EpCAM from being expressed at the cell surface. We demonstrate that C66Y and multiple other EpCAM cancer-associated mutations prevent surface expression of EpCAM. Cancer-associated mutations that prevent EpCAM cell surface expression abrogate the ability of EpCAM to inhibit CTSL activity and tumor cell invasion. Conclusions These studies reveal a novel role for EpCAM as a CTSL inhibitor, confirm the functional relevance of multiple cancer-associated EpCAM mutations, and suggest a therapeutic vulnerability in cancers harboring EpCAM mutations.

Melatonin modifies tumor hypoxia and metabolism by inhibiting HIF-1α and energy metabolic pathway in the in vitro and in vivo models of breast cancer

2019 ◽  
Vol 2 (4) ◽  
pp. 83-98 ◽  
Author(s):  
André De Lima Mota ◽  
Bruna Vitorasso Jardim-Perassi ◽  
Tialfi Bergamin De Castro ◽  
Jucimara Colombo ◽  
Nathália Martins Sonehara ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Glucose Metabolism ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Carbonic Anhydrases ◽  
In Vivo Models ◽  
Ca Ix ◽  
Gene And Protein Expression

Breast cancer is the most common cancer among women and has a high mortality rate. Adverse conditions in the tumor microenvironment, such as hypoxia and acidosis, may exert selective pressure on the tumor, selecting subpopulations of tumor cells with advantages for survival in this environment. In this context, therapeutic agents that can modify these conditions, and consequently the intratumoral heterogeneity need to be explored. Melatonin, in addition to its physiological effects, exhibits important anti-tumor actions which may associate with modification of hypoxia and Warburg effect. In this study, we have evaluated the action of melatonin on tumor growth and tumor metabolism by different markers of hypoxia and glucose metabolism (HIF-1α, glucose transporters GLUT1 and GLUT3 and carbonic anhydrases CA-IX and CA-XII) in triple negative breast cancer model. In an in vitro study, gene and protein expressions of these markers were evaluated by quantitative real-time PCR and immunocytochemistry, respectively. The effects of melatonin were also tested in a MDA-MB-231 xenograft animal model. Results showed that melatonin treatment reduced the viability of MDA-MB-231 cells and tumor growth in Balb/c nude mice (p <0.05). The treatment significantly decreased HIF-1α gene and protein expression concomitantly with the expression of GLUT1, GLUT3, CA-IX and CA-XII (p <0.05). These results strongly suggest that melatonin down-regulates HIF-1α expression and regulates glucose metabolism in breast tumor cells, therefore, controlling hypoxia and tumor progression. 

Current Challenges in the Development of Vaccines and Drugs Against Emerging Vector-borne Diseases

2019 ◽  
Vol 26 (16) ◽  
pp. 2974-2986 ◽  
Author(s):  
Kwang-sun Kim
Keyword(s):  
New Host ◽  
In Vivo Models ◽  
Vector Borne Diseases ◽  
Novel Drugs ◽  
Huge Impact ◽  
Tick Borne Disease ◽  
Vector Borne ◽  
Living Organisms

Vectors are living organisms that transmit infectious diseases from an infected animal to humans or another animal. Biological vectors such as mosquitoes, ticks, and sand flies carry pathogens that multiply within their bodies prior to delivery to a new host. The increased prevalence of Vector-Borne Diseases (VBDs) such as Aedes-borne dengue, Chikungunya (CHIKV), Zika (ZIKV), malaria, Tick-Borne Disease (TBD), and scrub typhus has a huge impact on the health of both humans and livestock worldwide. In particular, zoonotic diseases transmitted by mosquitoes and ticks place a considerable burden on public health. Vaccines, drugs, and vector control methods have been developed to prevent and treat VBDs and have prevented millions of deaths. However, development of such strategies is falling behind the rapid emergence of VBDs. Therefore, a comprehensive approach to fighting VBDs must be considered immediately. In this review, I focus on the challenges posed by emerging outbreaks of VBDs and discuss available drugs and vaccines designed to overcome this burden. Research into promising drugs needs to be upgraded and fast-tracked, and novel drugs or vaccines being tested in in vitro and in vivo models need to be moved into human clinical trials. Active preventive tactics, as well as new and upgraded diagnostics, surveillance, treatments, and vaccination strategies, need to be monitored constantly if we are to manage VBDs of medical importance.

Potential for Treatment of Neurodegenerative Diseases with Natural Products or Synthetic Compounds that Stabilize Microtubules

2020 ◽  
Vol 26 (35) ◽  
pp. 4362-4372
Author(s):  
John H. Miller ◽  
Viswanath Das
Keyword(s):  
Natural Products ◽  
Neurodegenerative Diseases ◽  
In Vivo Models ◽  
Synthetic Compounds ◽  
Stabilizing Agents ◽  
Animal Models Of Disease ◽  
Model Studies ◽  
Models Of Disease

No effective therapeutics to treat neurodegenerative diseases exist, despite significant attempts to find drugs that can reduce or rescue the debilitating symptoms of tauopathies such as Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, amyotrophic lateral sclerosis, or Pick’s disease. A number of in vitro and in vivo models exist for studying neurodegenerative diseases, including cell models employing induced-pluripotent stem cells, cerebral organoids, and animal models of disease. Recent research has focused on microtubulestabilizing agents, either natural products or synthetic compounds that can prevent the axonal destruction caused by tau protein pathologies. Although promising results have come from animal model studies using brainpenetrant natural product microtubule-stabilizing agents, such as paclitaxel analogs that can access the brain, epothilones B and D, and other synthetic compounds such as davunetide or the triazolopyrimidines, early clinical trials in humans have been disappointing. This review aims to summarize the research that has been carried out in this area and discuss the potential for the future development of an effective microtubule stabilizing drug to treat neurodegenerative disease.

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