Mutant p53 and Cellular Stress Pathways: A Criminal Alliance That Promotes Cancer Progression

The capability of cancer cells to manage stress induced by hypoxia, nutrient shortage, acidosis, redox imbalance, loss of calcium homeostasis and exposure to drugs is a key factor to ensure cancer survival and chemoresistance. Among the protective mechanisms utilized by cancer cells to cope with stress a pivotal role is played by the activation of heat shock proteins (HSP) response, anti-oxidant response induced by nuclear factor erythroid 2-related factor 2 (NRF2), the hypoxia-inducible factor-1 (HIF-1), the unfolded protein response (UPR) and autophagy, cellular processes strictly interconnected. However, depending on the type, intensity or duration of cellular stress, the balance between pro-survival and pro-death pathways may change, and cell survival may be shifted into cell death. Mutations of p53 (mutp53), occurring in more than 50% of human cancers, may confer oncogenic gain-of-function (GOF) to the protein, mainly due to its stabilization and interaction with the above reported cellular pathways that help cancer cells to adapt to stress. This review will focus on the interplay of mutp53 with HSPs, NRF2, UPR, and autophagy and discuss how the manipulation of these interconnected processes may tip the balance towards cell death or survival, particularly in response to therapies.

Download Full-text

Interplay between Endoplasmic Reticular Stress and Survivin in Colonic Epithelial Cells

Cells ◽

10.3390/cells7100171 ◽

2018 ◽

Vol 7 (10) ◽

pp. 171 ◽

Cited By ~ 8

Author(s):

Rohit Gundamaraju ◽

Ravichandra Vemuri ◽

Wai Chin Chong ◽

Stephen Myers ◽

Shaghayegh Norouzi ◽

...

Keyword(s):

Cell Death ◽

Cancer Cells ◽

Inflammatory Markers ◽

Caspase 3 ◽

Annexin V ◽

Parp Cleavage ◽

Cellular Survival ◽

Unfolded Protein ◽

Proliferative Assay ◽

The Unfolded Protein Response

Sustained endoplasmic reticular stress (ERS) is implicated in aggressive metastasis of cancer cells and increased tumor cell proliferation. Cancer cells activate the unfolded protein response (UPR), which aids in cellular survival and adaptation to harsh conditions. Inhibition of apoptosis, in contrast, is a mechanism adopted by cancer cells with the help of the inhibitor of an apoptosis (IAP) class of proteins such as Survivin to evade cell death and gain a proliferative advantage. In this study, we aimed to reveal the interrelation between ERS and Survivin. We initially verified the expression of Survivin in Winnie (a mouse model of chronic ERS) colon tissues by using immunohistochemistry (IHC) and immunofluorescence (IF) in comparison with wild type Blk6 mice. Additionally, we isolated the goblet cells and determined the expression of Survivin by IF and protein validation. Tunicamycin was utilized at a concentration of 10 µg/mL to induce ERS in the LS174T cell line and the gene expression of the ERS markers was measured. This was followed by determination of inflammatory cytokines. Inhibition of ERS was carried out by 4Phenyl Butyric acid (4PBA) at a concentration of 10 mM to assess whether there was a reciprocation effect. The downstream cell death assays including caspase 3/7, Annexin V, and poly(ADP-ribose) polymerase (PARP) cleavage were evaluated in the presence of ERS and absence of ERS, which was followed by a proliferative assay (EdU click) with and without ERS. Correspondingly, we inhibited Survivin by YM155 at a concentration of 100 nM and observed the succeeding ERS markers and inflammatory markers. We also verified the caspase 3/7 assay. Our results demonstrate that ERS inhibition not only significantly reduced the UPR genes (Grp78, ATF6, PERKandXBP1) along with Survivin but also downregulated the inflammatory markers such as IL8, IL4, and IL6, which suggests a positive correlation between ERS and the inhibition of apoptosis. Furthermore, we provided evidence that ERS inhibition promoted apoptosis in LS174T cells and shortened the proliferation rate. Moreover, Survivin inhibition by YM155 led to a comparable effect as that of ERS inhibition, which includes attenuation of ERS genes and inflammatory markers as well as the promotion of programmed cell death via the caspase 3/7 pathway. Together, our results propose the interrelation between ERS and inhibition of apoptosis assigning a molecular and therapeutic target for cancer treatment.

Download Full-text

G-Protein-Coupled Estrogen Receptor (GPER)-Specific Agonist G1 Induces ER Stress Leading to Cell Death in MCF-7 Cells

Biomolecules ◽

10.3390/biom9090503 ◽

2019 ◽

Vol 9 (9) ◽

pp. 503 ◽

Cited By ~ 5

Author(s):

Diep-Khanh Ho Vo ◽

Roland Hartig ◽

Sönke Weinert ◽

Johannes Haybaeck ◽

Norbert Nass

Keyword(s):

Cell Death ◽

Estrogen Receptor ◽

Er Stress ◽

G Protein ◽

Cancer Progression ◽

Cancer Cell Line ◽

Positive Breast Cancer Cell ◽

The Unfolded Protein Response ◽

G Protein Coupled ◽

Mcf 7

The G-protein-coupled estrogen receptor (GPER) mediates rapid non-genomic effects of estrogen. Although GPER is able to induce proliferation, it is down-regulated in breast, ovarian and colorectal cancer. During cancer progression, high expression levels of GPER are favorable for patients’ survival. The GPER-specific agonist G1 leads to an inhibition of cell proliferation and an elevated level of intracellular calcium (Ca2+). The purpose of this study is to elucidate the mechanism of G1-induced cell death by focusing on the connection between G1-induced Ca2+ depletion and endoplasmic reticulum (ER) stress in the estrogen receptor positive breast cancer cell line MCF-7. We found that G1-induced ER Ca2+ efflux led to the activation of the unfolded protein response (UPR), indicated by the phosphorylation of IRE1α and PERK and the cleavage of ATF6. The pro-survival UPR signaling was activated via up-regulation of the ER chaperon protein GRP78 and translational attenuation indicated by eIF2-α phosphorylation. However, the accompanying pro-death UPR signaling is profoundly activated and responsible for ER stress-induced cell death. Mechanistically, PERK-phosphorylation-induced JNK-phosphorylation and IRE1α-phosphorylation, which further triggered CAMKII-phosphorylation, are both implicated in G1-induced cell death. Our study indicates that loss of ER Ca2+ is responsible for G1-induced cell death via the pro-death UPR signaling.

Download Full-text

ROS Mediate xCT-Dependent Cell Death in Human Breast Cancer Cells under Glucose Deprivation

Cells ◽

10.3390/cells9071598 ◽

2020 ◽

Vol 9 (7) ◽

pp. 1598 ◽

Cited By ~ 2

Author(s):

Mei-Chun Chen ◽

Li-Lin Hsu ◽

Sheng-Fan Wang ◽

Chih-Yi Hsu ◽

Hsin-Chen Lee ◽

...

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Cancer Cells ◽

Cancer Progression ◽

Breast Cancer Cells ◽

Critical Role ◽

Glucose Deprivation ◽

Glutathione Biosynthesis ◽

Dependent Cell ◽

Amp Activated Protein Kinase

xCT, also known as solute carrier family 7 member 11 (SLC7A11), the light chain of the cystine/glutamate antiporter, is positively correlated with cancer progression due to antioxidant function. During glucose deprivation, the overexpression of xCT does not protect cancer cells but instead promotes cell death. Further understanding the mechanism of glucose deprivation-induced cell death is important for developing anticancer treatments targeting the glucose metabolism. In this study, we found that breast cancer cells with a high expression of xCT demonstrated increased levels of reactive oxygen species (ROS) and were more sensitive to glucose deprivation than the cells with a low expression of xCT. However, AMP-activated protein kinase (AMPK) did not significantly affect glucose-deprivation-induced cell death. The antioxidant N-acetyl-cysteine prevented glucose-deprivation-induced cell death, and the glutathione biosynthesis inhibitor L-buthionine-S, R-sulfoximine enhanced glucose-deprivation-induced cell death. The inhibition of xCT by sulfasalazine or a knockdown of xCT reduced the glucose-deprivation-increased ROS levels and glucose-deprivation-induced cell death. Glucose deprivation reduced the intracellular glutamate, and supplementation with α-ketoglutarate prevented the glucose-deprivation-increased ROS levels and rescued cell death. The knockdown of sirtuin-3 (SIRT3) further enhanced the ROS levels, and promoted xCT-related cell death after glucose deprivation. In conclusion, our results suggested that ROS play a critical role in xCT-dependent cell death in breast cancer cells under glucose deprivation.

Download Full-text

Is metronomic vinorelbine (mVRL) able to inhibit both HUVEC and triple-negative breast cancer (TNBC) cells? The proof-of-concept VICTOR-0 study.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e14014 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e14014-e14014

Author(s):

Maria Grazia Cerrito ◽

Davide Pelizzoni ◽

Marco De Giorgi ◽

Nunzio Digiacomo ◽

Marialuisa Lavitrano ◽

...

Keyword(s):

Breast Cancer ◽

Endothelial Cells ◽

Cell Death ◽

Cancer Cells ◽

Cancer Progression ◽

Umbilical Vein ◽

Metastatic Breast ◽

Proof Of Concept ◽

Proliferating Cells ◽

Drug Concentrations

e14014 Background: TNBC represents an important clinical challenge because of poor prognosis. One of the emerging strategy to achieve disease control while reducing toxicity is metronomic chemotherapy (mCHT) which targets the endothelial cells (ECs) and inhibits the tumor growth. mVRL is a promising option in patients (pts) with metastatic breast cancer (MBC), resulting in a median PFS of 7.7 months and median OS of 15.9. To better explain the effect of mVRL we studied the effects of metronomic doses of VRL in in vitro models and compared them with standard doses of the same drug. Methods: Cell viability and cytotoxicity assays were performed on TNBC cancer cells (MDA-MB-231) and Human Umbilical Vein Endothelial Cells (HUVEC). Cell lines were exposed to different concentration (0,01nM-1mM) of VRL for 4 and 96 h. To simulate the metronomic dosing schedule, we replaced the drug-enriched medium every 24h, while to simulate the conventional administration protocol (sCHT) cells were exposed to VRL for 4h, then the medium was changed and replaced with fresh medium without drug every 24 h. The IC50was calculated by non-linear regression fit of the mean values of data obtained in triplicate experiments. Results: A significant anti-proliferative activity was observed on both HUVEC and MDA cells treated with VRL in mCHT as compared to sCHT protocol (see Table). These lower drug concentrations did not have remarkable effects on cell death. Conversely, the higher dose utilized in sCHT produced important cell death in MDA as well as in HUVEC, even if in vivo, the higher dose of drug inducing the largest apoptosis of cancer cells also affectd healthy proliferating cells causing toxicity. Our findings suggest that mCHT inhibited the proliferation of both endothelial and tumour cells and can block cancer progression with minor side effects. Conclusions: This study provides the proof-of-concept that metronomic doses of VRL, but not the standard ones, are able to inhibit, at the same concentration, both the ECs and the TNBC cells. The clinical trial TEMPO-BREAST, which compares metronomic vs standard VRL, is ongoing in MBC pts. [Table: see text]

Download Full-text

HIF-1 — A BIG CHAPTER IN THE CANCER TALE

Experimental Oncology ◽

10.31768/2312-8852.2016.38(1):9-12 ◽

2016 ◽

Vol 38 (1) ◽

pp. 9-12 ◽

Cited By ~ 23

Author(s):

J Ajdukovic

Keyword(s):

Tumor Suppressor ◽

Tumor Progression ◽

Cancer Cells ◽

Cancer Progression ◽

Tumor Suppressor Genes ◽

Biological Effects ◽

Hypoxia Inducible Factor ◽

Signal Molecules ◽

Suppressor Genes ◽

Carcinoma Associated Fibroblasts

Approximately 1.0–1.5% of the genome is transcriptionally regulated by hypoxia, and hypoxia-inducible factor (HIF)-1α is the transcription factor modulating many of these genes. Cancer cells are able to survive hypoxic environments and hypoxia itself can activate adaptive cellular responses that contribute to tumor progression. Many HIF-1α-mediated biological effects are beneficial for tumor progression, including metabolic shift toward glycolysis, inhibition of fatty acid β-oxidation, production of cellular reacreactive oxygen species and altering expression of tumor suppressor genes. HIF-1 promotes selective mitochondrial autophagy, resisand altering expression of tumor suppressor genes. HIF-1 promotes selective mitochondrial autophagy, resistance to T cell mediated lysis of cancer cells, induction of pluripotent cancer stem cells, epithelial-mesenchymal and epithelialmesenchymal-endothelial transitions beneficial for tumor growth and progression, loss of E-cadherin. HIF-1 also induces production of signal molecules and cytokines by carcinoma-associated fibroblasts and upregulation of certain microRNAs important for cancer progression. This minireview focuses on the HIF-1 promoting role in tumor initiation and progression and HIF-1 targeting. HIF-1 pathway downregulation seems to be promising in future cancer treatment.

Download Full-text

Emerging Therapeutic Targets in Oncologic Photodynamic Therapy

Current Pharmaceutical Design ◽

10.2174/1381612825666190122163832 ◽

2019 ◽

Vol 24 (44) ◽

pp. 5268-5295 ◽

Cited By ~ 4

Author(s):

Gina Manda ◽

Mihail E. Hinescu ◽

Ionela V. Neagoe ◽

Luis F.V. Ferreira ◽

Rica Boscencu ◽

...

Keyword(s):

Cell Death ◽

Photodynamic Therapy ◽

Singlet Oxygen ◽

Cancer Cells ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Therapeutic Targets ◽

Molecular Networks ◽

Systems Medicine ◽

Therapeutic Tools

Background:Reactive oxygen species sustain tumorigenesis and cancer progression through deregulated redox signalling which also sensitizes cancer cells to therapy. Photodynamic therapy (PDT) is a promising anti-cancer therapy based on a provoked singlet oxygen burst, exhibiting a better toxicological profile than chemo- and radiotherapy. Important gaps in the knowledge on underlining molecular mechanisms impede on its translation towards clinical applications.Aims and Methods:The main objective of this review is to critically analyse the knowledge lately gained on therapeutic targets related to redox and inflammatory networks underlining PDT and its outcome in terms of cell death and resistance to therapy. Emerging therapeutic targets and pharmaceutical tools will be documented based on the identified molecular background of PDT.Results:Cellular responses and molecular networks in cancer cells exposed to the PDT-triggered singlet oxygen burst and the associated stresses are analysed using a systems medicine approach, addressing both cell death and repair mechanisms. In the context of immunogenic cell death, therapeutic tools for boosting anti-tumor immunity will be outlined. Finally, the transcription factor NRF2, which is a major coordinator of cytoprotective responses, is presented as a promising pharmacologic target for developing co-therapies designed to increase PDT efficacy.Conclusion:There is an urgent need to perform in-depth molecular investigations in the field of PDT and to correlate them with clinical data through a systems medicine approach for highlighting the complex biological signature of PDT. This will definitely guide translation of PDT to clinic and the development of new therapeutic strategies aimed at improving PDT.

Download Full-text

Tetraarsenic hexoxide enhances generation of mitochondrial ROS to promote pyroptosis by inducing the activation of caspase-3/GSDME in triple-negative breast cancer cells

Cell Death and Disease ◽

10.1038/s41419-021-03454-9 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Haein An ◽

Jin Sun Heo ◽

Pyunggang Kim ◽

Zenglin Lian ◽

Siyoung Lee ◽

...

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Cancer Cells ◽

Cancer Progression ◽

Triple Negative Breast Cancer ◽

Caspase 3 ◽

Triple Negative ◽

Tumor Formation ◽

Cell Swelling ◽

Mitochondrial Ros

AbstractAlthough tetraarsenic hexoxide is known to exert an anti-tumor effect by inducing apoptosis in various cancer cells, its effect on other forms of regulated cell death remains unclear. Here, we show that tetraarsenic hexoxide induces the pyroptotic cell death through activation of mitochondrial reactive oxygen species (ROS)-mediated caspase-3/gasdermin E (GSDME) pathway, thereby suppressing tumor growth and metastasis of triple-negative breast cancer (TNBC) cells. Interestingly, tetraarsenic hexoxide-treated TNBC cells exhibited specific pyroptotic characteristics, including cell swelling, balloon-like bubbling, and LDH releases through pore formation in the plasma membrane, eventually suppressing tumor formation and lung metastasis of TNBC cells. Mechanistically, tetraarsenic hexoxide markedly enhanced the production of mitochondrial ROS by inhibiting phosphorylation of mitochondrial STAT3, subsequently inducing caspase-3-dependent cleavage of GSDME, which consequently promoted pyroptotic cell death in TNBC cells. Collectively, our findings highlight tetraarsenic hexoxide-induced pyroptosis as a new therapeutic strategy that may inhibit cancer progression of TNBC cells.

Download Full-text

Modulating the unfolded protein response with ONC201 to impact on radiation response in prostate cancer cells

Scientific Reports ◽

10.1038/s41598-021-83215-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Francesca Amoroso ◽

Kimberley Glass ◽

Reema Singh ◽

Francisco Liberal ◽

Rebecca E. Steele ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Death ◽

Unfolded Protein Response ◽

Cancer Cells ◽

Radiation Response ◽

Prostate Cancer Cells ◽

Short Term Treatment ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

AbstractProstate cancer (PCa) is the most common non-cutaneous cancer in men and a notable cause of cancer mortality when it metastasises. The unfolded protein response (UPR) can be cytoprotective but when acutely activated can lead to cell death. In this study, we sought to enhance the acute activation of the UPR using radiation and ONC201, an UPR activator. Treating PCa cells with ONC201 quickly increased the expression of all the key regulators of the UPR and reduced the oxidative phosphorylation, with cell death occurring 72 h later. We exploited this time lag to sensitize prostate cancer cells to radiation through short-term treatment with ONC201. To understand how priming occurred, we performed RNA-Seq analysis and found that ONC201 suppressed the expression of cell cycle and DNA repair factors. In conclusion, we have shown that ONC201 can prime enhanced radiation response.

Download Full-text

HIF1-alpha expressing cells induce a hypoxic-like response in neighbouring cancer cells

10.1101/266213 ◽

2018 ◽

Author(s):

Hannah Harrison ◽

Henry J Pegg ◽

Jamie Thompson ◽

Christian Bates ◽

Paul Shore

Keyword(s):

Cancer Cells ◽

Cancer Progression ◽

Hypoxia Inducible Factor ◽

Experimental Models ◽

Metastatic Progression ◽

Low Oxygen ◽

Hypoxic Response ◽

Oxygen Levels ◽

Mammosphere Formation ◽

Cellular Environment

AbstractHypoxia stimulates metastasis in cancer and is linked to poor patient prognosis. In tumours, oxygen levels vary and hypoxic regions exist within a generally well-oxygenated tumour. However, whilst the heterogeneous environment is known to contribute to metastatic progression, little is known about the mechanism by which heterogeneic hypoxia contributes to cancer progression. This is largely because existing experimental models do not recapitulate the heterogeneous nature of hypoxia. The primary effector of the hypoxic response is the transcription factor Hypoxia inducible factor 1-alpha (HIF1-alpha). HIF1-alpha is stabilised in response to low oxygen levels in the cellular environment and its expression is seen in hypoxic regions throughout the tumour.We have developed a model system in which HIF1-alpha can be induced within a sub-population of cancer cells, thus enabling us to mimic the effects of heterogeneic HIF1-alpha expression.We show that induction of HIF1-alpha not only recapitulates elements of the hypoxic response in the induced cells but also results in significant changes in proliferation, gene expression and mammosphere formation within the HIF1-alpha negative population.These findings suggest that the HIF1-alpha expressing cells found within hypoxic regions are likely to contribute to the subsequent progression of a tumour by modifying the behaviour of cells in the non-hypoxic regions of the local micro-environment.

Download Full-text