Disruption of the unfolded protein response (UPR) by lead compound selectively suppresses cancer cell growth

Huang, Hejing; Liu, Huanan; Liu, Chang‐Mei; Fan, Lixia; Zhang, Xinwen; Gao, Anran; Hu, Xiaobei; Zhang, Kunzhi; Cao, Xianchao; Jiang, Kailong; Zhou, Yubo; Hou, Jian; Li, Jia

doi:10.1016/j.canlet.2015.02.029

Cited by 8 publications

(4 citation statements)

References 47 publications

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“…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. Indeed, there are numerous studies targeting UPR as a cancer therapy [27,30,37,48,[139][140][141]154,156,162,167,169], to increase chemotherapy efficacy [33,34,44,48,141,142,153,[159][160][161]165,[170][171][172], and to enhance immunotherapy [34,36,53,132,[173][174][175][176].…”

Section: Discussionmentioning

confidence: 99%

“…To date, several studies have shown that disrupting UPR signaling increases drug sensitivity. These include reports of abrogating UPR signaling with concurrent drug treatment in murine xenografts [156] and in vivo colorectal cancer models [157,158], and resensitizing breast cancer cells to chemotherapy and immunotherapy [35,36,43,45]. Alternatively, inducing UPR signaling sensitizes non-small-cell lung cancer to doxorubicin [159], instigates ovarian cancer cell death when paired with mifepristone [160], and increases the efficacy of viral antineoplastic therapies [161].…”

Section: Implications For Upr-targeting Drugs In Cancer Therapymentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Implications For Upr-targeting Drugs In Cancer Therapymentioning

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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“…In fact, the protective effect of mildly elevated levels of ERSR has been correlated to chemotherapeutic tolerance [11–13]. Attempts to block elevated basal levels of ERSR in cancer cells, mainly by inhibiting IRE1α, and subsequent splicing of its target XBP1, have been reported as potential anticancer therapeutics [14, 15]. However, further stimulation of ERSR beyond a critical point is accompanied by enhanced cell death, suggesting that potent ERSR-inducing agents may possess antineoplastic potential [13, 16–18].…”

Section: Introductionmentioning

confidence: 99%

A High-Throughput Screen Identifies 2,9-Diazaspiro[5.5]Undecanes as Inducers of the Endoplasmic Reticulum Stress Response with Cytotoxic Activity in 3D Glioma Cell Models

et al. 2016

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The endoplasmic reticulum (ER) is involved in Ca2+ signaling and protein folding. ER Ca2+ depletion and accumulation of unfolded proteins activate the molecular chaperone GRP78 (glucose-regulated protein 78) which in turn triggers the ER stress response (ERSR) pathway aimed to restore ER homeostasis. Failure to adapt to stress, however, results in apoptosis. We and others have shown that malignant cells are more susceptible to ERSR-induced apoptosis than their normal counterparts, implicating the ERSR as a potential target for cancer therapeutics. Predicated on these findings, we developed an assay that uses a GRP78 biosensor to identify small molecule activators of ERSR in glioma cells. We performed a quantitative high-throughput screen (qHTS) against a collection of ~425,000 compounds and a comprehensive panel of orthogonal secondary assays was formulated for stringent compound validation. We identified novel activators of ERSR, including a compound with a 2,9-diazaspiro[5.5]undecane core, which depletes intracellular Ca2+ stores and induces apoptosis-mediated cell death in several cancer cell lines, including patient-derived and 3D cultures of glioma cells. This study demonstrates that our screening platform enables the identification and profiling of ERSR inducers with cytotoxic activity and advocates for characterization of these compound in in vivo models.

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“…As illustrated in Figure 1, under physiological conditions, the luminal domains of BiP repress the activity of the three main stress sensors, PERK, IRE1, and ATF6, binding them (Crespo et al, 2012). However, ER lumen-accumulated unfolded proteins dissociate BiP from these effectors, which control the expression of downstream transcription factors: X-box binding protein (XBP)1 and ATF4 (Huang et al, 2015). These factors modulate the expression of chaperones or proteins involved in redox homeostasis, protein secretion or cell death programs (Senft and Ronai, 2015).…”

Section: Upr Activationmentioning

confidence: 99%

Endoplasmic Reticulum Unfolded Protein Response, Aging and Exercise: An Update

et al. 2018

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The endoplasmic reticulum (ER) is a dynamic and multifunctional organelle responsible for protein biosynthesis, folding, assembly and modifications. Loss of protein folding regulation, which leads to unfolded or misfolded proteins accumulation inside the ER lumen, drives ER stress (ERS) and unfolded protein response (UPR) activation. During aging, there is a decline in the ability of the cell to handle protein folding, accumulation and aggregation, and the function of UPR is compromised. There is a progressive failure of the chaperoning systems and a decline in many of its components, so that the UPR activation cannot rescue the ERS. Physical activity has been proposed as a powerful tool against aged-related diseases, which are linked to ERS. Interventional studies have demonstrated that regular exercise is able to decrease oxidative stress and inflammation and reverse mitochondrial and ER dysfunctions. Exercise-induced metabolic stress could activate the UPR since muscle contraction is directly involved in its activation, mediating exercise-induced adaptation responses. In fact, regular moderate-intensity exercise-induced ERS acts as a protective mechanism against current and future stressors. However, biological responses vary according to exercise intensity and therefore induce different degrees of ERS and UPR activation. This article reviews the effects of aging and exercise on ERS and UPR, also analyzing possible changes induced by different types of exercise in elderly subjects.

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Disruption of the unfolded protein response (UPR) by lead compound selectively suppresses cancer cell growth

Cited by 8 publications

References 47 publications

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

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

A High-Throughput Screen Identifies 2,9-Diazaspiro[5.5]Undecanes as Inducers of the Endoplasmic Reticulum Stress Response with Cytotoxic Activity in 3D Glioma Cell Models

Endoplasmic Reticulum Unfolded Protein Response, Aging and Exercise: An Update

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