Targeting the GRP78 Pathway for Cancer Therapy

Lu, Guanhua; Luo, Hui; Zhu, Xiao

doi:10.3389/fmed.2020.00351

Cited by 61 publications

(47 citation statements)

References 56 publications

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“…For example, decreasing HSPA5 expression would be the potentials to prevent COVID-19, especially those with malignant tumors. Indeed, HSPA5 has been recently implied as an anticancer drug target 8 , 110 , 111 . We might consider the treatment potentials such as using HSPA5 inhibitors 112 .…”

Section: Discussionmentioning

confidence: 99%

“…Dysregulations of these stress proteins including HSPA5 are associated with many human diseases including cancers, immunological diseases, cardiovascular diseases, neurodegenerative diseases, obesity, stroke and infectious diseases 3 - 6 . Targeting HSPA5 may be potential in therapy for human diseases 7 , 8 as well as COVID-19 (Coronavirus Disease 2019) 9 - 11 .…”

Section: Introductionmentioning

confidence: 99%

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Evaluation and characterization of HSPA5 (GRP78) expression profiles in normal individuals and cancer patients with COVID-19

Fu¹,

Wei²,

He³

et al. 2021

Int. J. Biol. Sci.

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HSPA5 (BiP, GRP78) has been reported as a potential host-cell receptor for SARS-Cov-2, but its expression profiles on different tissues including tumors, its susceptibility to SARS-Cov-2 virus and severity of its adverse effects on malignant patients are unclear. In the current study, HSPA5 has been found to be expressed ubiquitously in normal tissues and significantly increased in 14 of 31 types of cancer tissues. In lung cancer, mRNA levels of HSPA5 were 253-fold increase than that of ACE2 . Meanwhile, in both malignant tumors and matched normal samples across almost all cancer types, mRNA levels of HSPA5 were much higher than those of ACE2 . Higher expression of HSPA5 significantly decreased patient overall survival (OS) in 7 types of cancers. Moreover, systematic analyses found that 7.15% of 5,068 COVID-19 cases have malignant cancer coincidental situations, and the rate of severe events of COVID-19 patients with cancers present a higher trend than that for all COVID-19 patients, showing a significant difference (33.33% vs 16.09%, p <0.01). Collectively, these data imply that the tissues with high HSPA5 expression, not low ACE2 expression, are susceptible to be invaded by SARS-CoV-2. Taken together, this study not only indicates the clinical significance of HSPA5 in COVID-19 disease and cancers, but also provides potential clues for further medical treatments and managements of COVID-19 patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evaluation and characterization of HSPA5 (GRP78) expression profiles in normal individuals and cancer patients with COVID-19

Fu¹,

Wei²,

He³

et al. 2021

Int. J. Biol. Sci.

View full text Add to dashboard Cite

show abstract

“…HSPA5 refers to the gene that encodes GRP78 or BiP protein, a key chaperone for newly synthesized proteins, supporting cotranslational modifications, which is an essential component of the UPR and an important target to cancer therapy (Wang et al, 2009;Lu et al, 2020). As a matter of fact, GRP78, a member of the HSP70 family of proteins, is the common initial response that detaches and activates the downstream ER-stress sensors, therefore a typical marker to UPR (Kopp et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Marine Streptomyces sp. Isolated From the Brazilian Endemic Tunicate Euherdmania sp. Produces Dihydroeponemycin and Analogs With Potent Antiglioma Activity

et al. 2021

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Marine natural products have emerged as an important source for drug development, notably in the field of anticancer therapy. Still, the limited effectiveness of current therapies for central nervous system tumors indicates the need to identify new therapeutic targets and also novel pharmacological agents. In this context, proteasome inhibitors are appearing as a promising new treatment for these diseases. Herein, cytotoxic extracts produced by four marine bacteria recovered from the Brazilian endemic ascidian Euherdmania sp. were screened to evaluate their potential as proteasome inhibitors. The extract from marine Streptomyces sp. BRA-346 was selected for further investigation due to the potent proteasome inhibitory activity it displayed. Bioassay-guided fractionation led to an enriched fraction (proteasome inhibition IC50 = 45 ng/mL), in which the presence of dihydroeponemycin (DHE), known for its proteasome inhibitory effect, and related compounds were annotated by mass spectrometry and further confirmed by comparison with DHE standard. Both DHE and the epoxyketone-containing fraction were evaluated in glioma cell lines, displaying high cytotoxicity in HOG and T98G cells (GI50 of 1.6 and 1.7 ng/mL for DHE, and 17.6 and 28.2 ng/mL for the BRA-346 fraction, respectively). Additional studies showed that the epoxyketone-containing fraction (at GI50 levels) led to an accumulation of ubiquitinated proteins and up-regulation of genes related to ER-stress response, suggesting treated cells are under proteasome inhibition. DHE induced similar effects in treated cells but at concentrations 25 times its GI50, suggesting that the other epoxyketone compounds in the bacteria extract derived fraction may contribute to enhance proteasome inhibition and further cellular effects in glioma cells. These findings revealed the molecular pathways modulated by this class of compounds in glioma cells and, moreover, reinforced the potential of this marine bacteria in producing a cocktail of structurally-related compounds that affect the viability of glioma cells.

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“…Generally, the higher the mutation load, the higher the possibility of producing MHC-bond peptides. Inhibitory immune cells (such as tumorassociated macrophages) and tumor-causing inflammatory mediators (such as TNF-a、 IL-6、 TGF-b) in tumor microenvironment can stimulate tumor cell proliferation and induce tumor angiogenesis by inhibiting NF-kB and STAT3 signaling pathways, promote the tumor immune escape as well as the tumor invasion and metastasis (45)(46)(47).…”

Section: Checkpoint Inhibitormentioning

confidence: 99%

The Mechanism of Stimulating and Mobilizing the Immune System Enhancing the Anti-Tumor Immunity

Zhu

2021

Front. Immunol.

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Cancer immunotherapy is a kind of therapy that can control and eliminate tumors by restarting and maintaining the tumor-immune cycle and restoring the body’s normal anti-tumor immune response. Although immunotherapy has great potential, it is currently only applicable to patients with certain types of tumors, such as melanoma, lung cancer, and cancer with high mutation load and microsatellite instability, and even in these types of tumors, immunotherapy is not effective for all patients. In order to enhance the effectiveness of tumor immunotherapy, this article reviews the research progress of tumor microenvironment immunotherapy, and studies the mechanism of stimulating and mobilizing immune system to enhance anti-tumor immunity. In this review, we focused on immunotherapy against tumor microenvironment (TME) and discussed the important research progress. TME is the environment for the survival and development of tumor cells, which is composed of cell components and non-cell components; immunotherapy for TME by stimulating or mobilizing the immune system of the body, enhancing the anti-tumor immunity. The checkpoint inhibitors can effectively block the inhibitory immunoregulation, indirectly strengthen the anti-tumor immune response and improve the effect of immunotherapy. We also found the checkpoint inhibitors have brought great changes to the treatment model of advanced tumors, but the clinical treatment results show great individual differences. Based on the close attention to the future development trend of immunotherapy, this study summarized the latest progress of immunotherapy and pointed out a new direction. To study the mechanism of stimulating and mobilizing the immune system to enhance anti-tumor immunity can provide new opportunities for cancer treatment, expand the clinical application scope and effective population of cancer immunotherapy, and improve the survival rate of cancer patients.

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Targeting the GRP78 Pathway for Cancer Therapy

Cited by 61 publications

References 56 publications

Evaluation and characterization of HSPA5 (GRP78) expression profiles in normal individuals and cancer patients with COVID-19

Evaluation and characterization of HSPA5 (GRP78) expression profiles in normal individuals and cancer patients with COVID-19

Marine Streptomyces sp. Isolated From the Brazilian Endemic Tunicate Euherdmania sp. Produces Dihydroeponemycin and Analogs With Potent Antiglioma Activity

The Mechanism of Stimulating and Mobilizing the Immune System Enhancing the Anti-Tumor Immunity

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