scholarly journals Targeting Cancer Metabolism Breaks Radioresistance by Impairing the Stress Response

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3762
Author(s):  
Melissa Schwab ◽  
Katharina Thunborg ◽  
Omid Azimzadeh ◽  
Christine von Toerne ◽  
Caroline Werner ◽  
...  
Keyword(s):  
Stress Response ◽  
Heat Shock ◽  
Tumor Cells ◽  
Cancer Metabolism ◽  
Glucose Deprivation ◽  
Therapy Resistance ◽  
Hsp70 Expression ◽  
Heat Shock Factor 1 ◽  
Double Knockout ◽  
Ldh Activity

The heightened energetic demand increases lactate dehydrogenase (LDH) activity, the corresponding oncometabolite lactate, expression of heat shock proteins (HSPs) and thereby promotes therapy resistance in many malignant tumor cell types. Therefore, we assessed the coregulation of LDH and the heat shock response with respect to radiation resistance in different tumor cells (B16F10 murine melanoma and LS174T human colorectal adenocarcinoma). The inhibition of LDH activity by oxamate or GNE-140, glucose deprivation and LDHA/B double knockout (LDH−/−) in B16F10 and LS174T cells significantly diminish tumor growth; ROS production and the cytosolic expression of different HSPs, including Hsp90, Hsp70 and Hsp27 concomitant with a reduction of heat shock factor 1 (HSF1)/pHSF1. An altered lipid metabolism mediated by a LDHA/B double knockout results in a decreased presence of the Hsp70-anchoring glycosphingolipid Gb3 on the cell surface of tumor cells, which, in turn, reduces the membrane Hsp70 density and increases the extracellular Hsp70 levels. Vice versa, elevated extracellular lactate/pyruvate concentrations increase the membrane Hsp70 expression in wildtype tumor cells. Functionally, an inhibition of LDH causes a generalized reduction of cytosolic and membrane-bound HSPs in tumor cells and significantly increases the radiosensitivity, which is associated with a G2/M arrest. We demonstrate that targeting of the lactate/pyruvate metabolism breaks the radioresistance by impairing the stress response.

scholarly journals Disruption of Heat Shock Factor 1 Reveals an Essential Role in the Ubiquitin Proteolytic Pathway

2000 ◽  
Vol 20 (8) ◽  
pp. 2670-2675 ◽  
Author(s):  
Lila Pirkkala ◽  
Tero-Pekka Alastalo ◽  
XiaoXia Zuo ◽  
Ivor J. Benjamin ◽  
Lea Sistonen
Keyword(s):  
Stress Response ◽  
Heat Shock ◽  
Hsp70 Expression ◽  
Heat Shock Factor 1 ◽  
Loss Of Function ◽  
Down Regulation ◽  
Proteolytic Pathway ◽  
Ubiquitin Proteasome ◽  
A Cell ◽  
Shock Proteins

ABSTRACT Inhibition of proteasome-mediated protein degradation machinery is a potent stress stimulus that causes accumulation of ubiquitinated proteins and increased expression of heat shock proteins (Hsps). Hsps play pivotal roles in homeostasis and protection in a cell, through their well-recognized properties as molecular chaperones. The inducible Hsp expression is regulated by the heat shock transcription factors (HSFs). Among mammalian HSFs, HSF1 has been shown to be important for regulation of the heat-induced stress gene expression, whereas the function of HSF2 in stress response is unclear. Recent reports have suggested that both HSF1 and HSF2 are affected during down-regulation of ubiquitin-proteasome pathway (Y. Kawazoe et al., Eur. J. Biochem. 255:356–362, 1998; A. Mathew et al., Mol. Cell. Biol. 18:5091–5098, 1998; D. Kim et al., Biochem. Biophys. Res. Commun. 254:264–268, 1999). To date, however, no unambiguous evidence has been presented as to whether a single specific HSF or multiple members of the HSF family are required for transcriptional induction of heat shock genes when proteasome activity is down-regulated. Therefore, by using loss-of-function and gain-of-function strategies, we investigated the specific roles of mammalian HSFs in regulation of the ubiquitin-proteasome-mediated stress response. Here we demonstrate that HSF1, but not HSF2, is essential and sufficient for up-regulation of Hsp70 expression during down-regulation of the ubiquitin proteolytic pathway. We propose that specificity of HSF1 could be an important therapeutic target during disease pathogenesis associated with abnormal ubiquitin-dependent proteasome function.

scholarly journals Roles of Extracellular HSPs as Biomarkers in Immune Surveillance and Immune Evasion

2019 ◽  
Vol 20 (18) ◽  
pp. 4588 ◽  
Author(s):  
Eman A. Taha ◽  
Kisho Ono ◽  
Takanori Eguchi
Keyword(s):  
Heat Shock ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Immune Evasion ◽  
Checkpoint Inhibitors ◽  
Membrane Surface ◽  
Immune Surveillance ◽  
Heat Shock Factor 1 ◽  
Heterochromatin Protein 1 ◽  
Liquid Biopsies

Extracellular heat shock proteins (ex-HSPs) have been found in exosomes, oncosomes, membrane surfaces, as well as free HSP in cancer and various pathological conditions, also known as alarmins. Such ex-HSPs include HSP90 (α, β, Gp96, Trap1), HSP70, and large and small HSPs. Production of HSPs is coordinately induced by heat shock factor 1 (HSF1) and hypoxia-inducible factor 1 (HIF-1), while matrix metalloproteinase 3 (MMP-3) and heterochromatin protein 1 are novel inducers of HSPs. Oncosomes released by tumor cells are a major aspect of the resistance-associated secretory phenotype (RASP) by which immune evasion can be established. The concepts of RASP are: (i) releases of ex-HSP and HSP-rich oncosomes are essential in RASP, by which molecular co-transfer of HSPs with oncogenic factors to recipient cells can promote cancer progression and resistance against stresses such as hypoxia, radiation, drugs, and immune systems; (ii) RASP of tumor cells can eject anticancer drugs, targeted therapeutics, and immune checkpoint inhibitors with oncosomes; (iii) cytotoxic lipids can be also released from tumor cells as RASP. ex-HSP and membrane-surface HSP (mHSP) play immunostimulatory roles recognized by CD91+ scavenger receptor expressed by endothelial cells-1 (SREC-1)+ Toll-like receptors (TLRs)+ antigen-presenting cells, leading to antigen cross-presentation and T cell cross-priming, as well as by CD94+ natural killer cells, leading to tumor cytolysis. On the other hand, ex-HSP/CD91 signaling in cancer cells promotes cancer progression. HSPs in body fluids are potential biomarkers detectable by liquid biopsies in cancers and tissue-damaged diseases. HSP-based vaccines, inhibitors, and RNAi therapeutics are also reviewed.

scholarly journals Multifactorial Attenuation of the Murine Heat Shock Response With Age

2019 ◽  
Vol 75 (10) ◽  
pp. 1846-1852 ◽  
Author(s):  
Donald A Jurivich ◽  
Gunjan D Manocha ◽  
Rachana Trivedi ◽  
Mary Lizakowski ◽  
Sharlene Rakoczy ◽  
...  
Keyword(s):  
Stress Response ◽  
Heat Shock ◽  
Protein Interactions ◽  
Messenger Rna ◽  
Physiological Stress ◽  
Cellular Stress Response ◽  
Heat Shock Factor 1 ◽  
Protein Levels ◽  
Age Related ◽  
Age Dependent

Abstract Age-dependent perturbation of the cellular stress response affects proteostasis and other key functions relevant to cellular action and survival. Central to age-related changes in the stress response is loss of heat shock factor 1 (HSF1)–DNA binding and transactivation properties. This report elucidates how age alters different checkpoints of HSF1 activation related to posttranslational modification and protein interactions. When comparing liver extracts from middle aged (12 M) and old (24 M) mice, significant differences are found in HSF1 phosphorylation and acetylation. HSF1 protein levels and messenger RNA decline with age, but its protein levels are stress-inducible and exempt from age-dependent changes. This surprising adaptive change in the stress response has additional implications for aging and chronic physiological stress that might explain an age-dependent dichotomy of HSF1 protein levels that are low in neurodegeneration and elevated in cancer.

scholarly journals Roles of Extracellular Vesicles (EVs) Carrying HSPs in Cancer Biomarkers, Immune Surveillance, and Immune Evasion

2019 ◽  
Author(s):  
Eman Taha ◽  
Kisho Ono ◽  
Takanori Eguchi
Keyword(s):  
Heat Shock ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Immune Evasion ◽  
Checkpoint Inhibitors ◽  
Immune Surveillance ◽  
Heat Shock Factor 1 ◽  
Targeted Therapeutics ◽  
Heterochromatin Protein 1

Extracellular vesicles (EV) released by tumor cells are a major aspect of the resistance-associated secretory phenotype (RASP), by which immune evasion can be established. Heat shock proteins (HSPs) are an evolutionarily conserved family of molecular chaperones, which stabilize proteins, minimize protein misfolding and aggregation within the cell, besides facilitating protein translocation, refolding and degradation. (i) Releases of extracellular HSPs (ex-HSP) and EV-associated HSPs (EV-HSP) are essential in RASP, by which molecular cotransfer of HSPs with oncogenic factors into recipient cells can promote cancer progression and resistance against stress such as hypoxia, radiation, chemicals, and immune system. (ii) RASP of tumor cells can eject anticancer drugs, molecularly targeted therapeutics, and immune checkpoint inhibitors with EVs. (iii) Cytotoxic lipids can be also released from tumor cells as RASP. Nevertheless, ex-HSP and EV-HSP can play immunostimulatory and immunosuppressive roles by binding to receptors such as LRP1/CD91/A2MR, scavenger receptors, and toll-like receptors expressed on recipient cells. Liquid biopsy of HSPs in body fluids may be useful in diagnosis, prognosis, and treatment in cancer. Regarding HSP90-targeted therapeutics, we summarize the pros, cons, and problem solutions in this review. Although production of HSPs are canonically induced by heat shock factor 1 (HSF1) and hypoxia-inducible factor 1 (HIF-1), recent studies discovered that production of HSPs is also regulated by matrix metalloproteinase 3 (MMP3) and heterochromatin protein 1 (HP1) and production of cochaperone CDC37 is reciprocally regulated by myeloid zinc finger 1 (MZF1) and SCAN-D1.

scholarly journals Physiological Fever Temperature Induces a Protective Stress Response in T Lymphocytes Mediated by Heat Shock Factor-1 (HSF1)

2007 ◽  
Vol 179 (12) ◽  
pp. 8305-8312 ◽  
Author(s):  
Patience Murapa ◽  
Siva Gandhapudi ◽  
Hollie S. Skaggs ◽  
Kevin D. Sarge ◽  
Jerold G. Woodward
Keyword(s):  
Stress Response ◽  
Heat Shock ◽  
T Lymphocytes ◽  
Heat Shock Factor ◽  
Heat Shock Factor 1

scholarly journals Heat shock factor 1 is a key regulator of the stress response in Chlamydomonas

2007 ◽  
Vol 52 (2) ◽  
pp. 286-295 ◽  
Author(s):  
Miriam Schulz-Raffelt ◽  
Mukesh Lodha ◽  
Michael Schroda
Keyword(s):  
Stress Response ◽  
Heat Shock ◽  
Heat Shock Factor ◽  
Heat Shock Factor 1

Tissue-specific expression of zebrafish (Danio rerio) heat shock factor 1 mRNAs in response to heat stress

2000 ◽  
Vol 203 (12) ◽  
pp. 1817-1824 ◽  
Author(s):  
C.M. Rabergh ◽  
S. Airaksinen ◽  
A. Soitamo ◽  
H.V. Bjorklund ◽  
T. Johansson ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Heat Stress ◽  
Stress Response ◽  
Heat Shock ◽  
Danio Rerio ◽  
Stress Proteins ◽  
Heat Shock Transcription Factor ◽  
Heat Shock Factor 1 ◽  
Tissue Specific ◽  
Mammalian Cell Lines

All organisms respond to environmental, chemical and physiological stresses by enhanced synthesis of an evolutionarily conserved family of proteins known as heat shock proteins (HSPs) or stress proteins. Certain HSPs are also expressed constitutively during cell growth and development, and they function as molecular chaperones. The transcriptional regulation of hsp genes is mediated by the heat shock transcription factor (HSF). The stress response has been studied mostly in mammalian cell lines or organisms normally maintained under constant laboratory conditions. There is much less information on the regulation of the stress response of animals, such as fish, that have to tolerate large fluctuations in environmental and internal conditions. To characterize the regulation of the heat shock response in fish, we have cloned the first heat shock transcription factor from fish, zebrafish Danio rerio. Phylogenetic analysis confirms that the isolated zebrafish HSF belongs to the HSF1 family and is therefore designated zHSF1. Analysis by reverse transcriptase polymerase chain reaction (RT-PCR) shows the presence of two zHSF1 mRNA forms that are expressed in a tissue-specific fashion upon exposure to heat stress. Both forms are expressed in gonads under all conditions; in liver and to a lesser extent in the gills, the longer splice form of zHSF1 disappears upon heat shock. We present evidence for a unique tissue-specific regulation of HSF1 upon exposure to elevated temperature.

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