Feedback loop between hypoxia and energy metabolic reprogramming aggravates the radioresistance of cancer cells

Experimental Hematology and Oncology, Journal Year: 2024, Volume and Issue: 13(1)

Published: May 22, 2024

Abstract Radiotherapy is one of the mainstream approaches for cancer treatment, although clinical outcomes are limited due to radioresistance tumor cells. Hypoxia and metabolic reprogramming hallmarks initiation progression closely linked radioresistance. Inside a tumor, rate angiogenesis lags behind cell proliferation, underdevelopment abnormal functions blood vessels in some loci result oxygen deficiency cells, i.e., hypoxia. This prevents radiation from effectively eliminating hypoxic Cancer cells switch glycolysis as main source energy, phenomenon known Warburg effect, sustain their rapid proliferation rates. Therefore, pathways involved hypoxia-induced promising intervention targets treatment. In this review, we discussed mechanisms underlying hypoxia detail, including DNA repair, role stem oxidative stress relief, autophagy regulation, immune escape. addition, proposed existence feedback loop between energy hypoxia, which associated with development exacerbation tumors. Simultaneous blockade other tumor-specific can be an effective approach overcome comprehensive overview provides new insights into radiosensitivity progression.

Language: Английский

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The HSP90 inhibitor HVH-2930 exhibits potent efficacy against trastuzumab-resistant HER2-positive breast cancer

Theranostics, Journal Year: 2024, Volume and Issue: 14(6), P. 2442 - 2463

Published: Jan. 1, 2024

Rationale: Resistance to targeted therapies like trastuzumab remains a critical challenge for HER2-positive breast cancer patients.Despite the progress of several N-terminal HSP90 inhibitors in clinical trials, none have achieved approval use, primarily due issues such as induction heat shock response (HSR), off-target effects, and unfavorable toxicity profiles.We sought examine effects HVH-2930, novel C-terminal inhibitor, overcoming resistance.Methods: The effect HVH-2930 on trastuzumab-sensitive -resistant cell lines vitro was evaluated terms viability, expression client proteins, impact stem cells.An vivo model with trastuzumab-resistant JIMT-1 cells used efficacy HVH-2930.Results: rationally designed fit into ATP-binding pocket interface cavity hHSP90 homodimer domain HSP90, stabilizing its open conformation hindering ATP binding.HVH-2930 induces apoptosis without inducing HSR but by specifically suppressing HER2 signaling pathway.This occurs downregulation HER2/p95HER2 disruption family member heterodimerization.Attenuation (CSC)-like properties associated stemness factors ALDH1, CD44, Nanog Oct4.Furthermore, administration inhibited angiogenesis tumor growth xenograft mice.A synergistic observed when combining paclitaxel xenografts.Conclusion: Our findings highlight potent resistance cancer.Further investigation is warranted fully establish therapeutic potential.

Language: Английский

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Understanding Cervical Cancer through Proteomics

Cells, Journal Year: 2021, Volume and Issue: 10(8), P. 1854 - 1854

Published: July 22, 2021

Cancer is one of the leading public health issues worldwide, and number cancer patients increases every day. Particularly, cervical (CC) still second cause death in women from developing countries. Thus, it essential to deepen our knowledge about molecular pathogenesis CC propose new therapeutic targets methods diagnose this disease its early stages. Differential expression analysis using high-throughput techniques applied biological samples allows determining physiological state normal cells changes produced by development. The cluster differential profiles genome, transcriptome, or proteome analyzed disease, called signature cancer. Proteomic with different grades intraepithelial neoplasia (CIN) has served elucidate pathways involved development progression identify proteins associated CC. However, several carcinogenesis mechanisms are unclear. Detecting pathologies their earliest stages can significantly improve a patient’s survival rate, prognosis, recurrence. present review an update on proteomic study

Language: Английский

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Evodiamine inhibits both stem cell and non-stem-cell populations in human cancer cells by targeting heat shock protein 70

Theranostics, Journal Year: 2021, Volume and Issue: 11(6), P. 2932 - 2952

Published: Jan. 1, 2021

Rationale: Cancer stem cells (CSCs) are known to cause tumor recurrence and drug resistance. The heat shock protein (HSP) system plays a major role in preserving expression function of numerous oncoproteins, including those involved the CSC activities. We explored novel anticancer drugs, especially targeting HSP components required for functional CSCs. Methods: Investigation CSCs screening natural product chemical library were performed by utilizing cancer cell lines, primary cultures patient-derived xenografts (PDXs), their putative subpopulations (i.e., grown under sphere-forming conditions, stably transfected with reporter vectors carrying NANOG or POUSF1 promoters, high ALDH activity) vitro PDX KrasG12D/+-driven models vivo. Regulation was investigated immunoprecipitation, affinity responsive target stability assay, binding experiments using ATP-agarose beads biotinylated drug, docking analysis. Results: activated via transcriptional upregulation components, HSP70. Evodiamine (Evo) identified induce apoptosis both bulk non-CSC populations human lung, colon, breast sublines chemoresistance. Evo administration decreased multiplicity, volume, load lung tumors KrasG12D/+ transgenic mice growth line- PDX-derived without detectable toxicity. Mechanistically, disrupted N-terminal ATP-binding pocket HSP70 causing its ubiquitin-mediated degradation. Conclusions: Our findings illustrate as potential eliminating an effective HSP70-targeting eradicating non-CSCs minimal

Language: Английский

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The Role of Hsp27 in Chemotherapy Resistance

Biomedicines, Journal Year: 2022, Volume and Issue: 10(4), P. 897 - 897

Published: April 14, 2022

Heat shock protein (Hsp)-27 is a small-sized, ATP-independent, chaperone molecule that overexpressed under conditions of cellular stress such as oxidative and heat shock, protects proteins from unfolding, thus facilitating proteostasis survival. Despite its protective role in normal cell physiology, Hsp27 overexpression various cancer lines implicated tumor initiation, progression, metastasis through mechanisms, including modulation the SWH pathway, inhibition apoptosis, promotion EMT, adaptation CSCs microenvironment induction angiogenesis. Investigation resistance types against doxorubicin, herceptin/trastuzumab, gemcitabine, 5-FU, temozolomide, paclitaxel suggested promotes survival above-mentioned chemotherapeutic agents. Conversely, increased efficacy those chemotherapy drugs, both vitro vivo. Although numerous signaling pathways molecular mechanisms were resistance, most commonly contributed to upregulation Akt/mTOR cascade inactivation p53, inhibiting chemotherapy-mediated apoptosis. Blockage could enhance cytotoxic effect well-established especially difficult-to-treat types, ultimately improving patients’ outcomes.

Language: Английский

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Factors and molecular mechanisms of radiation resistance in cancer cells

International Journal of Radiation Biology, Journal Year: 2022, Volume and Issue: 98(8), P. 1301 - 1315

Published: Feb. 28, 2022

The aim of this work is to review the published studies on radiation resistance mechanisms and molecular markers involved in different tumors. revision has been focused last 5 years (2016-2021).Radioresistance a cause concern as it causes failure therapy subsequent tumor relapse. Combination chemotherapy are clinically successful treating many types Despite continued improvements cancer treatment, locoregional recurrence or metastatic spread continues occur high proportion patients after being treated with combination treatments. There strong evidence that stem cells contribute resistance, contributing treatment failure. tumors not fully understood. A better understanding associated signaling pathways regulate will open up new strategies for by therapy. Radiation can damage malignant mainly induction DNA double-strand breaks. However, some appear resistant repopulate following leading over time treatment. Native induced resistance. It described numerous acting through action such apoptosis alterations cell growth, proliferation repair, hypoxia, increase invasiveness migration capacity, cycle alterations, expression heat shock proteins, among others. Therefore, multifactorial phenomenon that, types, occurs regulatory which molecules intervene. Resistance be acquired altering knowledge could help classification more aggressive

Language: Английский

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The multifunction of HSP70 in cancer: Guardian or traitor to the survival of tumor cells and the next potential therapeutic target

International Immunopharmacology, Journal Year: 2023, Volume and Issue: 122, P. 110492 - 110492

Published: June 28, 2023

Language: Английский

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Heat Shock Proteins Mediate Intercellular Communications within the Tumor Microenvironment through Extracellular Vesicles

Applied Biosciences, Journal Year: 2024, Volume and Issue: 3(1), P. 45 - 58

Published: Jan. 1, 2024

From an evolutive perspective, tumor cells endure successive turnover upon stress conditions and pressure to adapt new environments. These use exceptional communication skills share biological information “survive every metabolic cost”. The microenvironment (TME) is a miscellaneous collection of cells, factors, extracellular vesicles (EVs). EVs are small lipid bilayer-delimited particles derived from with sizes ranging 100 1000 nm. Exosomes (<160 nm) the minor subtype EVs, originating endosomal pathways. TME also contains “giant” vesicles, microvesicles (100–1000 nm, MV), originated membrane blebbing. can act as intercellular mediators, contributing many processes, by carrying different biomolecules, such proteins, lipids, nucleic acids, metabolites. EV secretion promote either cell survival or manage their death. Tumor-derived transfer adaptative signaling recipient reprograming these cells. Heat shock proteins (HSP) prominent response regulators, specifically carried exosomes. HSP-loaded reprogram acquire mechanisms progression therapy resistance. mediated favors escape endoplasmic reticulum stress, hypoxia, apoptosis, anticancer therapies. Extracellular HSPs activate deactivate immune response, induce differentiation, change vascular homeostasis, help augment pre-metastatic niche formation. Here we explore EVs’ HSP transmission among relevance communications in resistance therapy.

Language: Английский

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Cell surface GRP78 promotes stemness in normal and neoplastic cells

Scientific Reports, Journal Year: 2020, Volume and Issue: 10(1)

Published: Feb. 26, 2020

Reliable approaches to identify stem cell mechanisms that mediate aggressive cancer could have great therapeutic value, based on the growing evidence of embryonic signatures in metastatic cancers. However, how best and target stem-like aberrantly acquired by cells has been challenging. We harnessed power reprogramming examine GRP78, a chaperone protein generally restricted endoplasmic reticulum normal tissues, but which is expressed surface human many types. discovered (1) GRP78 (sGRP78) iPSCs important reprogramming, (2) sGRP78 promotes cellular functions both pluripotent breast (3) overexpression leads an induction CD24-/CD44+ tumor initiating (TIC) population (4) sGRP78+ are enriched for stemness genes appear be subset TICs (5) show enhanced ability seed organ sites vivo. These collective findings regulating pluripotency oncogenesis, suggest marks increased potential

Language: Английский

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HSP70s in Breast Cancer: Promoters of Tumorigenesis and Potential Targets/Tools for Therapy

Cells, Journal Year: 2021, Volume and Issue: 10(12), P. 3446 - 3446

Published: Dec. 7, 2021

The high frequency of breast cancer worldwide and the mortality among women with this malignancy are a serious challenge for modern medicine. A deeper understanding mechanisms carcinogenesis emergence metastatic, therapy-resistant cancers would help development novel approaches to better treatment disease. review is dedicated role members heat shock protein 70 subfamily (HSP70s or HSPA), mainly inducible HSP70, glucose-regulated 78 (GRP78 HSPA5) GRP75 (HSPA9 mortalin), in pathogenesis cancer. Various HSP70-mediated cellular pathways which contribute oncogenic transformation mammary gland epithelium reviewed, as well their human carcinomas invasive, metastatic traits along resistance host immunity conventional therapeutics. Additionally, intracellular cell surface HSP70s considered potential targets therapy sensitization We also discuss clinical implication Hsp70s targeting gene vectors nanoparticles downregulating HSP70s, natural synthetic (small molecule) inhibitors HSP70-binding antibodies, HSP70-derived peptides, HSP70-based vaccines.

Language: Английский

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