Anastasis and the ER stress response: Solving the paradox of the unfolded protein response in cancer

Manalo, Rafael Vincent M.

doi:10.1016/j.mehy.2017.09.013

Cited by 8 publications

(9 citation statements)

References 34 publications

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“…Signatures of surviving cells from previous non-apocalyptic chemotherapeutic treatments did not match that of PAMEs: 0/9 and 2/11 genes described in Tang et al (2012;2017), 3/37 in Berthenet et al (2020), and <1% (4/759 late UP genes and 19/2,210 UP genes by at least 2-fold) described in Sun et al (2017) were also UP in PAMEs. Indeed, only 3/31 genes (SNAIL1, VIM, and IL32) mentioned in this subsection were similarly regulated in a previous study (Sun et al, 2017).…”

Section: Enhanced Expression Of Secreted Stemness and Metastatic Repr...mentioning

confidence: 88%

“…(1) Cells surviving an impending or near-death experience display high ER stress (Figure 7E) enhanced by the engaged processes (e.g., apoptosis, ferroptosis, and EMT; Feng et al, 2014;Zeindl-Eberhart et al, 2014;Dixon et al, 2014;Urra et al, 2016;Manalo, 2017). Such impending death may also be triggered by oncogenic, hypoxia, or drug-treatment events through ER stress involving PERK-CHOP (Tabas and Ron, 2011;Oakes, 2020;Hetz et al, 2020) (Figure 7E).…”

Section: Discussionmentioning

confidence: 99%

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On the origin of metastases: Induction of pro-metastatic states after impending cell death via ER stress, reprogramming, and a cytokine storm

2022

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Section: Enhanced Expression Of Secreted Stemness and Metastatic Repr...mentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

On the origin of metastases: Induction of pro-metastatic states after impending cell death via ER stress, reprogramming, and a cytokine storm

2022

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“…Despite the development of novel therapeutic approaches against human cardiovascular and cancer diseases, effective interventions will require determining the mechanisms that regulate cell fate decisions during cellular stress conditions. The problem, however, is that the molecular crosstalk between these pathways remains largely unexplained and limited to cancer cell models [ 51 , 52 , 53 , 54 , 55 , 56 , 57 ]. Notably, despite the fact that hypoxia has been reported to activate UPR signaling in order to modulate cancer progression [ 5 , 54 , 58 , 59 ], the cancer cell-based models often rely on unique genetic and epigenetic modifications that allow these cells to bypass cell fate decisions during both hypoxia and the UPR.…”

Section: Discussionmentioning

confidence: 99%

IRE1 Endoribonuclease Activity Modulates Hypoxic HIF-1α Signaling in Human Endothelial Cells

2020

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While the role of hypoxia and the induction of the hypoxia inducible factors (HIFs) and the unfolded protein response (UPR) pathways in the cancer microenvironment are well characterized, their roles and relationship in normal human endothelium are less clear. Here, we examined the effects of IRE1 on HIF-1α protein levels during hypoxia in primary human umbilical vein endothelial cells (HUVECs). The results demonstrated that HIF-1α levels peaked at 6 h of hypoxia along with two of their target genes, GLUT1 and VEGFA, whereas at up to 12 h of hypoxia the mRNA levels of markers of the UPR, IRE1, XBP1s, BiP, and CHOP, did not increase, suggesting that the UPR was not activated. Interestingly, the siRNA knockdown of IRE1 or inhibition of IRE1 endonuclease activity with 4µ8C during hypoxia significantly reduced HIF-1α protein without affecting HIF1A mRNA expression. The inhibition of the endonuclease activity with 4µ8C in two other primary endothelial cells during hypoxia, human cardiac microvascular endothelial cells and human aortic endothelial cells showed the same reduction in the HIF-1α protein. Surprisingly, the siRNA knockdown of XBP1s during hypoxia did not decrease the HIF1α protein levels, indicating that the IRE1-mediated effect on stabilizing the HIF1α protein levels was XBP1s-independent. The studies presented here, therefore, provide evidence that IRE1 activity during hypoxia increases the protein levels of HIF1α in an XBP1s-independent manner.

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“…UPR regulates immune function both in induction of pathogen response and inhibition of autoimmunity [164]. Another context in which UPR is of particular interest is tumor development and tumor microenvironment [21,23,29,31,32,39,48,[165][166][167][168]. The role of UPR has been investigated in many types of cancer, suggesting that targeting UPR will be a viable strategy regardless of cancer origin and mutations.…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic Reticulum Stress Pathway, the Unfolded Protein Response, Modulates Immune Function in the Tumor Microenvironment to Impact Tumor Progression and Therapeutic Response

Ramirez

Hernandez²,

Soto-Pantoja

et al. 2019

IJMS

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Despite advances in cancer therapy, several persistent issues remain. These include cancer recurrence, effective targeting of aggressive or therapy-resistant cancers, and selective treatments for transformed cells. This review evaluates the current findings and highlights the potential of targeting the unfolded protein response to treat cancer. The unfolded protein response, an evolutionarily conserved pathway in all eukaryotes, is initiated in response to misfolded proteins accumulating within the lumen of the endoplasmic reticulum. This pathway is initially cytoprotective, allowing cells to survive stressful events; however, prolonged activation of the unfolded protein response also activates apoptotic responses. This balance is key in successful mammalian immune response and inducing cell death in malignant cells. We discuss how the unfolded protein response affects cancer progression, survival, and immune response to cancer cells. The literature shows that targeting the unfolded protein response as a monotherapy or in combination with chemotherapy or immunotherapies increases the efficacy of these drugs; however, systemic unfolded protein response targeting may yield deleterious effects on immune cell function and should be taken into consideration. The material in this review shows the promise of both approaches, each of which merits further research.

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Anastasis and the ER stress response: Solving the paradox of the unfolded protein response in cancer

Cited by 8 publications

References 34 publications

On the origin of metastases: Induction of pro-metastatic states after impending cell death via ER stress, reprogramming, and a cytokine storm

On the origin of metastases: Induction of pro-metastatic states after impending cell death via ER stress, reprogramming, and a cytokine storm

IRE1 Endoribonuclease Activity Modulates Hypoxic HIF-1α Signaling in Human Endothelial Cells

Endoplasmic Reticulum Stress Pathway, the Unfolded Protein Response, Modulates Immune Function in the Tumor Microenvironment to Impact Tumor Progression and Therapeutic Response

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