Targeting the unfolded protein response in head and neck and oral cavity cancers

Cole, Daniel; Svider, Peter F.; Shenouda, Kerolos; Lee, Paul B.; Yoo, Nicholas; McLeod, Thomas M.; Mutchnick, Sean; Yoo, George H.; Kaufman, Randal J.; Callaghan, Michael U.; Fribley, Andrew M.

doi:10.1016/j.yexcr.2019.04.007

Cited by 12 publications

(7 citation statements)

References 265 publications

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“…Because of the highly secretory nature of cancer cells, it has been suggested that cancer cells may have a lower threshold for the activation of ER stress induced cell death. Various chemical or natural products were reported to enhance ER stress and to exert a UPR-dependent cytotoxic effect in HNSCC (summarized in Table 1) [94]. Some HIV protease inhibitors such as lopinavir and ritonavir have been shown to radiosensitize HNSCC cell lines by inducing ER stress/UPR-induced cell death [95].…”

Section: The Upr As a Therapeutic Targetmentioning

confidence: 99%

Impact and Relevance of the Unfolded Protein Response in HNSCC

Pluquet

Galmiche

2019

IJMS

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Head and neck squamous cell carcinomas (HNSCC) encompass a heterogeneous group of solid tumors that arise from the upper aerodigestive tract. The tumor cells face multiple challenges including an acute demand of protein synthesis often driven by oncogene activation, limited nutrient and oxygen supply and exposure to chemo/radiotherapy, which forces them to develop adaptive mechanisms such as the Unfolded Protein Response (UPR). It is now well documented that the UPR, a homeostatic mechanism, is induced at different stages of cancer progression in response to intrinsic (oncogenic activation) or extrinsic (microenvironment) perturbations. This review will discuss the role of the UPR in HNSCC as well as in the key processes that characterize the physiology of HNSCC. The role of the UPR in the clinical context of HNSCC will also be addressed.

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Section: The Upr As a Therapeutic Targetmentioning

confidence: 99%

Impact and Relevance of the Unfolded Protein Response in HNSCC

Pluquet

Galmiche

2019

IJMS

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“…The 78-kDa glucose-regulated protein (GRP78/BiP), a molecular chaperone of the heat shock protein 70 family, participates in biological functions that are relevant to a poor response to cancer therapy, in particular the control of the unfolded protein response (UPR) via activation of transmembrane ER-stress sensor proteins and calcium storage (5,6). In HNSCC and other tumor types, the UPR is constantly activated by numerous stressors of the tumor microenvironment such as hypoxia or nutrient deprivation (7,8) leading to an upregulation of GRP78 expression in tumor cells which is considerably higher compared to non-malignant cells. Besides accumulating in the ER to counter ER stress, a function in tumor cell signaling and communication is suggested as GRP78 is translocated to the cell surface of tumor cells upon different cellular stressors such as hypoxia (9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

The Chaperone Protein GRP78 Promotes Survival and Migration of Head and Neck Cancer After Direct Radiation Exposure and Extracellular Vesicle-Transfer

et al. 2022

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Background and PurposeIncreased levels of the chaperone protein GRP78 have been implicated in poorer outcomes of cancer therapy. We have therefore explored the functional connection between the expression of GRP78 and the development of radioresistance and metastatic behavior in HNSCC.Material and MethodsThe association between gene expression of GRP78 and survival in HNSCC patients was examined using the TCGA database. The influence of ionizing radiation on the GRP78 levels in HNSCC cell lines, their secreted extracellular vesicles (EV) and non-irradiated EV-recipient cells was investigated by Western Blot and FACS. The consequences of chemical inhibition or experimental overexpression of GRP78 on radioresistance and migration of HNSCC cells were analyzed by clonogenic survival and gap closure assays.ResultsElevated levels of GRP78 RNA in HNSCC correlated with poorer overall survival. Radiation increased GRP78 protein expression on the surface of HNSCC cell lines. Experimental overexpression of GRP78 increased both radioresistance and migratory potential. Chemical inhibition of GRP78 impaired cell migration. EVs were identified as a potential source of increased GRP78 content as elevated levels of surface GRP78 were found in EVs released by irradiated cells. These vesicles transferred GRP78 to non-irradiated recipient cells during co-cultivation.ConclusionsWe have identified the chaperone protein GRP78 as a potential driver of increased radioresistance and motility in HNSCC. The uptake of GRP78-rich EVs originating from irradiated cells may contribute to a poorer prognosis through bystander effects mediated by the transfer of GRP78 to non-irradiated cells. Therefore, we consider the chaperone protein GRP78 to be an attractive target for improving radiotherapy strategies.

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“…It is known that the phosphorylation of S6, a ribosomal protein involved in translation, is closely associated with global translational activation 35 . It is worth mentioning previous reports that the regulation of ER stress is identified as a mechanism for the anti‐cancer effects of dasatinib in head and neck cancers 65,66 . Since dasatinib increased the expression of GRP78 and the phosphorylation of eIF‐2α while decreasing the phosphorylation of S6 in YD‐38 cells, induction of ER stress and global translational inhibition in YD‐38 cells may therefore contribute to the drug's growth‐suppressive and pro‐apoptotic effects.…”

Section: Discussionmentioning

confidence: 96%

Anti‐growth and pro‐apoptotic effects of dasatinib on human oral cancer cells through multi‐targeted mechanisms

Park

Yadav

et al. 2021

J Cellular Molecular Medi

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Dasatinib is an inhibitor of Src that has anti‐tumour effects on many haematological and solid cancers. However, the anti‐tumour effects of dasatinib on human oral cancers remain unclear. In this study, we investigated the effects of dasatinib on different types of human oral cancer cells: the non‐tumorigenic YD‐8 and YD‐38 and the tumorigenic YD‐10B and HSC‐3 cells. Strikingly, dasatinib at 10 µM strongly suppressed the growth and induced apoptosis of YD‐38 cells and inhibited the phosphorylation of Src, EGFR, STAT‐3, STAT‐5, PKB and ERK‐1/2. In contrast, knockdown of Src blocked the phosphorylation of EGFR, STAT‐5, PKB and ERK‐1/2, but not STAT‐3, in YD‐38 cells. Dasatinib induced activation of the intrinsic caspase pathway, which was inhibited by z‐VAD‐fmk, a pan‐caspase inhibitor. Dasatinib also decreased Mcl‐1 expression and S6 phosphorylation while increased GRP78 expression and eIF‐2α phosphorylation in YD‐38 cells. In addition, to its direct effects on YD‐38 cells, dasatinib also exhibited anti‐angiogenic properties. Dasatinib‐treated YD‐38 or HUVEC showed reduced HIF‐1α expression and stability. Dasatinib alone or conditioned media from dasatinib‐treated YD‐38 cells inhibited HUVEC tube formation on Matrigel without affecting HUVEC viability. Importantly, dasatinib's anti‐growth, anti‐angiogenic and pro‐apoptotic effects were additionally seen in tumorigenic HSC‐3 cells. Together, these results demonstrate that dasatinib has strong anti‐growth, anti‐angiogenic and pro‐apoptotic effects on human oral cancer cells, which are mediated through the regulation of multiple targets, including Src, EGFR, STAT‐3, STAT‐5, PKB, ERK‐1/2, S6, eIF‐2α, GRP78, caspase‐9/3, Mcl‐1 and HIF‐1α.

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Targeting the unfolded protein response in head and neck and oral cavity cancers

Cited by 12 publications

References 265 publications

Impact and Relevance of the Unfolded Protein Response in HNSCC

Impact and Relevance of the Unfolded Protein Response in HNSCC

The Chaperone Protein GRP78 Promotes Survival and Migration of Head and Neck Cancer After Direct Radiation Exposure and Extracellular Vesicle-Transfer

Anti‐growth and pro‐apoptotic effects of dasatinib on human oral cancer cells through multi‐targeted mechanisms

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