Emerging roles of endoplasmic reticulum stress in the cellular plasticity of cancer cells

Abstract

Cellular plasticity is a well-known dynamic feature of tumor cells that endows tumors with heterogeneity and therapeutic resistance and alters their invasion–metastasis progression, stemness, and drug sensitivity, thereby posing a major challenge to cancer therapy. It is becoming increasingly clear that endoplasmic reticulum (ER) stress is a hallmark of cancer. The dysregulated expression of ER stress sensors and the activation of downstream signaling pathways play a role in the regulation of tumor progression and cellular response to various challenges. Moreover, mounting evidence implicates ER stress in the regulation of cancer cell plasticity, including epithelial–mesenchymal plasticity, drug resistance phenotype, cancer stem cell phenotype, and vasculogenic mimicry phenotype plasticity. ER stress influences several malignant characteristics of tumor cells, including epithelial-to-mesenchymal transition (EMT), stem cell maintenance, angiogenic function, and tumor cell sensitivity to targeted therapy. The emerging links between ER stress and cancer cell plasticity that are implicated in tumor progression and chemoresistance are discussed in this review, which may aid in formulating strategies to target ER stress and cancer cell plasticity in anticancer treatments.

Extracellular vimentin as a modulator of the immune response and an important player during infectious diseases

“…In some infections, pathogens or immune responses can lead to the upregulation and release of vimentin into the extracellular space 28,40,42–45 . Various forms of cellular stress, such as oxidative or endoplasmic reticulum (ER) stress, have also been associated with vimentin upregulation, potentially increasing its extracellular pool during cell activation or injuries 46,47 …”

Unveiling the mechanisms and challenges of cancer drug resistance

“…Moderate ER stress induction is correlated to the activation of the pro-survival genes that regulates amino acid metabolism, ER chaperones, redox reaction, protein folding, and autophagy [ 361 ]. In some cases..of cancer like in HCC, it has been found that endoplasmic reticulum stress-mediated activation of autophagy also plays a role in upregulating MRP1 that enhances intracellular drug or toxic heavy metal efflux thus protecting cells from apoptosis [ 362 , 363 ]. Autophagy is shown to influence some crucial drug-resistant enzymes (detoxifying enzymes) like aldehyde dehydrogenase (ALD1A3) and thus arbitrate in acquired drug resistance in temozolomide-treated human glioblastoma cells [ 141 ].…”

ER Stress-Activated HSF1 Governs Cancer Cell Resistance to USP7 Inhibitor-Based Chemotherapy through the PERK Pathway

“…Activation of cellular adaptation mechanisms, such as the UPR, against ER stress is known to promote the plasticity of cancer cells, thus dynamically regulating the metastasis, recurrence, evasion of antitumor immunity, and chemoresistance of tumors [ 13 , 14 ]. ER stress and the UPR are tightly regulated by three ER transmembrane proteins, the inositol-requiring enzyme 1 (IRE1), protein kinase R-like ER kinase (PERK), and activating transcription factor 6 (ATF6), which are UPR sensor proteins [ 15 ].…”