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Targeting the GRP78 Pathway for Cancer Therapy.

ABSTRACT: The 78-kDa glucose-regulated protein (GRP78) plays an important part in maintaining protein stability, regulating protein folding, and inducing apoptosis autophagy, which is considered as a powerful protein. Meanwhile, it also plays a role in ensuring the normal function of organs. In recent years, more and more researches have been carried out on the targeted therapy of GRP78, mainly focusing on its relevant role in tumor and its role as a major modulator and modulator of subordinate pathways. The ability of GRP78 to respond to endoplasmic reticulum stress (ERS) determines whether tumor cells survive and whether the changes in expression level of GRP78 regulated by endoplasmic reticulum (ER) caused by various factors will directly or indirectly affect cell proliferation, apoptosis, and injury, or reduce the body's defense ability, or have protective effects on various organs.

SUBMITTER: Lu G

PROVIDER: S-EPMC7409388 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Targeting the GRP78 Pathway for Cancer Therapy.

Lu Guanhua G Luo Hui H Zhu Xiao X

Frontiers in medicine 20200730

The 78-kDa glucose-regulated protein (GRP78) plays an important part in maintaining protein stability, regulating protein folding, and inducing apoptosis autophagy, which is considered as a powerful protein. Meanwhile, it also plays a role in ensuring the normal function of organs. In recent years, more and more researches have been carried out on the targeted therapy of GRP78, mainly focusing on its relevant role in tumor and its role as a major modulator and modulator of subordinate pathways. ...[more]

PMID: 32850882

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Project description:Glucose-regulated protein 78 (GRP78) is an endoplasmic reticulum (ER)-resident chaperone and a major regulator of the unfolded protein response (UPR). Accumulating evidence indicate that GRP78 is overexpressed in many cancer cell lines, and contributes to the invasion and metastasis in many human tumors. Besides, GRP78 upregulation is detected in response to different ER stress-inducing anticancer therapies, including photodynamic therapy (PDT). This study demonstrates that GRP78 mRNA and protein levels are elevated in response to PDT in various cancer cell lines. Stable overexpression of GRP78 confers resistance to PDT substantiating its cytoprotective role. Moreover, GRP78-targeting subtilase cytotoxin catalytic subunit fused with epidermal growth factor (EGF-SubA) sensitizes various cancer cells to Photofrin-mediated PDT. The combination treatment is cytotoxic to apoptosis-competent SW-900 lung cancer cells, as well as to Bax-deficient and apoptosis-resistant DU-145 prostate cancer cells. In these cells, PDT and EGF-SubA cytotoxin induce protein kinase R-like ER kinase and inositol-requiring enzyme 1 branches of UPR and also increase the level of C/EBP (CCAAT/enhancer-binding protein) homologous protein, an ER stress-associated apoptosis-promoting transcription factor. Although some apoptotic events such as disruption of mitochondrial membrane and caspase activation are detected after PDT, there is no phosphatidylserine plasma membrane externalization or DNA fragmentation, suggesting that in DU-145 cells the late apoptotic events are missing. Moreover, in SW-900 cells, EGF-SubA cytotoxin potentiates PDT-mediated cell death but attenuates PDT-induced apoptosis. In addition, the cell death cannot be reversed by caspase inhibitor z-VAD, confirming that apoptosis is not a major cell death mode triggered by the combination therapy. Moreover, no typical features of necrotic or autophagic cell death are recognized. Instead, an extensive cellular vacuolation of ER origin is observed. Altogether, these findings indicate that PDT and GRP78-targeting cytotoxin treatment can efficiently kill cancer cells independent on their apoptotic competence and triggers an atypical, non-apoptotic cell death.

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Targeting the GRP78 Pathway for Cancer Therapy.

Publications

Targeting the GRP78 Pathway for Cancer Therapy.

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