Integrated stress response is critical for gemcitabine resistance in pancreatic ductal adenocarcinoma

Palam, Lakshmi Reddy; Gore, Jesse; Craven, Kelly E.; Wilson, Julie L.; Korc, Murray

doi:10.1038/cddis.2015.264

Cited by 106 publications

(86 citation statements)

References 63 publications

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“…In contrast to the direction explored here, replication stress can also induce the ISR, as has been reported in the case of the nucleoside analogue gemcitabine (49). Of note, however, gemcitabine was found to induce eIF2alpha phosphorylation with a delay of at least 6 hours.…”

Section: Discussioncontrasting

confidence: 55%

The integrated stress response induces R-loops and hinders replication fork progression

Choo

Schloesser

Manzini

et al. 2020

Preprint

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The integrated stress response (ISR) allows cells to rapidly shut down most of their protein synthesis in response to protein misfolding, amino acid deficiency, or virus infection. These stresses trigger the phosphorylation of the translation initiation factor eIF2alpha, which prevents the initiation of translation. Here we show that triggering the ISR drastically reduces the progression of DNA replication forks within one hour, thus flanking the shutdown of protein synthesis with immediate inhibition of DNA synthesis. DNA replication is restored by compounds that inhibit eIF2alpha kinases or reactivate eIF2alpha. Mechanistically, the translational shutdown blocks histone synthesis, promoting the formation of DNA:RNA hybrids (R-loops) which interfere with DNA replication. Histone depletion alone induces R-loops and compromises DNA replication. Conversely, histone overexpression or R-loop removal by RNaseH1 each restores DNA replication in the context of ISR and histone depletion. In conclusion, the ISR rapidly stalls DNA synthesis through histone deficiency and R-loop formation. We propose that this shutdown mechanism prevents potentially detrimental DNA replication in the face of cellular stresses. SIGNIFICANCE The integrated stress response has long been explored regarding its immediate impact on protein synthesis. Translational shutdown represents an indispensable mechanism to prevent the toxicity of misfolded proteins and virus infections. Our results indicate that the shutdown mechanisms reach far beyond translation and immediately interfere with DNA synthesis as well. ISR depletes cells of new histones which induce accumulation of DNA:RNA hybrids. The impairment of DNA replication in this context supports cell survival during stress.Our work provides a link between the ISR and another subject of active research, i. e. the regulatory network of DNA replication forks.

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Section: Discussioncontrasting

confidence: 55%

The integrated stress response induces R-loops and hinders replication fork progression

Choo

Schloesser

Manzini

et al. 2020

Preprint

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“…ISRIB reverses stress‐induced mRNA translation repression and inhibits stress granule formation, enhancing stress‐induced apoptosis as a result of a defective stress response in tumour cells . Preclinical studies using a pancreatic ductal adenocarcinoma model showed promising anti‐tumour activity for ISRIB .…”

Section: Targeting the Translational Machinery In Cancermentioning

confidence: 99%

Translational control of aberrant stress responses as a hallmark of cancer

El-Naggar

Sorensen

2018

The Journal of Pathology

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Altered mRNA translational control is emerging as a critical factor in cancer development and progression. Targeting specific elements of the translational machinery, such as mTORC1 or eIF4E, is emerging as a new strategy for innovative cancer therapy. While translation of most mRNAs takes place through cap-dependent mechanisms, a sub-population of cellular mRNA species, particularly stress-inducible mRNAs with highly structured 5'-UTR regions, are primarily translated through cap-independent mechanisms. Intriguingly, many of these mRNAs encode proteins that are involved in tumour cell adaptation to microenvironmental stress, and thus linked to aggressive behaviour including tumour invasion and metastasis. This necessitates a rigorous search for links between microenvironmental stress and aggressive tumour phenotypes. Under stress, cells block global protein synthesis to preserve energy while maintaining selective synthesis of proteins that support cell survival. One highly conserved mechanism to regulate protein synthesis under cell stress is to sequester mRNAs into cytosolic aggregates called stress granules (SGs), where their translation is silenced. SGs confer survival advantages and chemotherapeutic resistance to tumour cells under stress. Recently, it has been shown that genetically blocking SG formation dramatically reduces tumour invasive and metastatic capacity in vivo. Therefore, targeting SG formation might represent a potential treatment strategy to block cancer metastasis. Here, we present the critical link between selective mRNA translation, stress adaptation, SGs, and tumour progression. Further, we also explain how deciphering mechanisms of selective mRNA translation occurs under cell stress holds great promise for the identification of new targets in the treatment of cancer.

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“…One mechanism for cancer cells to combat chemotherapy is to use a protective stress response (Jaramillo and Zhang 2013;Sui et al 2013;Palam et al 2015). The validated SMYD2 targets (i.e., RB, p53, HSP90, PARP1, PTEN, HSP90, and MAPKAPK3) are involved at some level in stress signaling, which led us to postulate that activation of SMYD2 might represent one mechanism regulating the response of PDAC cells to chemotherapy.…”

Section: Smyd2 Inhibition Enhances the Effects Of Chemotherapy In Pdacmentioning

confidence: 99%

Coordination of stress signals by the lysine methyltransferase SMYD2 promotes pancreatic cancer

et al. 2016

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Pancreatic ductal adenocarcinoma (PDAC) is a lethal form of cancer with few therapeutic options. We found that levels of the lysine methyltransferase SMYD2 (SET and MYND domain 2) are elevated in PDAC and that genetic and pharmacological inhibition of SMYD2 restricts PDAC growth. We further identified the stress response kinase MAPKAPK3 (MK3) as a new physiologic substrate of SMYD2 in PDAC cells. Inhibition of MAPKAPK3 impedes PDAC growth, identifying a potential new kinase target in PDAC. Finally, we show that inhibition of SMYD2 cooperates with standard chemotherapy to treat PDAC cells and tumors. These findings uncover a pivotal role for SMYD2 in promoting pancreatic cancer.

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Integrated stress response is critical for gemcitabine resistance in pancreatic ductal adenocarcinoma

Cited by 106 publications

References 63 publications

The integrated stress response induces R-loops and hinders replication fork progression

The integrated stress response induces R-loops and hinders replication fork progression

Translational control of aberrant stress responses as a hallmark of cancer

Coordination of stress signals by the lysine methyltransferase SMYD2 promotes pancreatic cancer

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