Molecular Stressors Engender Protein Connectivity Dysfunction through Aberrant N-Glycosylation of a Chaperone

Yan, Pengrong; Patel, Hardik J.; Sharma, Sahil; Corben, Adriana D.; Wang, Tai; Panchal, Palak; Yang, Chenghua; Sun, Weilin; Araujo, Thaís L.S.; Rodina, Anna; Joshi, Suhasini; Robzyk, Kenneth; Gandu, Srinivasa; White, Julie R.; Stanchina, Elisa de; Modi, Shanu; Janjigian, Yelena Y.; Hill, Elizabeth G.; Liu, Bei; Erdjument‐Bromage, Hediye; Neubert, Thomas A.; Que, Nanette L.S.; Li, Zihai; Gewirth, D.T.; Taldone, Tony; Chiosis, Gabriela

doi:10.1016/j.celrep.2020.107840

Cited by 37 publications

(100 citation statements)

References 86 publications

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“…Recently, Yan et al discovered that GRP94 adopt a unique hyperglycosylated conformation to preferentially regulate growth factor receptors on tumor cells. GRP94 specific inhibitor PU-WS13 favorably binds to hyperglycosylated GRP94 and inhibits RTK-driven tumor growth (66). Selective inhibition of GRP94 is still a feasible targeted therapy.…”

Section: Discussionmentioning

confidence: 99%

Molecular Chaperone GRP94/GP96 in Cancers: Oncogenesis and Therapeutic Target

et al. 2021

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During tumor development and progression, intrinsic and extrinsic factors trigger endoplasmic reticulum (ER) stress and the unfolded protein response, resulting in the increased expression of molecular chaperones to cope with the stress and maintain tumor cell survival. Heat shock protein (HSP) GRP94, also known as GP96, is an ER paralog of HSP90 and has been shown to promote survival signaling during tumor-induced stress and modulate the immune response through its multiple clients, including TLRs, integrins, LRP6, GARP, IGF, and HER2. Clinically, elevated expression of GRP94 correlates with an aggressive phenotype and poor clinical outcome in a variety of cancers. Thus, GRP94 is a potential molecular marker and therapeutic target in malignancies. In this review, we will undergo deep molecular profiling of GRP94 in tumor development and summarize the individual roles of GRP94 in common cancers, including breast cancer, colon cancer, lung cancer, liver cancer, multiple myeloma, and others. Finally, we will briefly review the therapeutic potential of selectively targeting GRP94 for the treatment of cancers.

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Section: Discussionmentioning

confidence: 99%

Molecular Chaperone GRP94/GP96 in Cancers: Oncogenesis and Therapeutic Target

et al. 2021

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“…Alterations in protein–protein interaction networks are thought to be at the core of malignant transformation [ 132 ]. It is also thought that stress may remodel the proteome by both enhancing of interaction affinity of the chaperone complement as well as by switching interaction partner combinations, thus leading to proteome-wide connectivity dysfunctions [ 133 ]. How stress modulates a chaperome to alter protein–protein interactions in cancer remains yet to be fully explored.…”

Section: Heroes or Villains: The Role Of Heat Shock Proteins In Prmentioning

confidence: 99%

“…How stress modulates a chaperome to alter protein–protein interactions in cancer remains yet to be fully explored. It was recently established that N-glycosylation of the ER-resident Hsp90 chaperone, Grp94, during stress led to global remodelling of cellular protein networks [ 133 ].…”

Section: Heroes or Villains: The Role Of Heat Shock Proteins In Prmentioning

confidence: 99%

The Role of Non-Canonical Hsp70s (Hsp110/Grp170) in Cancer

Chakafana

Shonhai

2021

Cells

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Although cancers account for over 16% of all global deaths annually, at present, no reliable therapies exist for most types of the disease. As protein folding facilitators, heat shock proteins (Hsps) play an important role in cancer development. Not surprisingly, Hsps are among leading anticancer drug targets. Generally, Hsp70s are divided into two main subtypes: canonical Hsp70 (Escherichia coli Hsp70/DnaK homologues) and the non-canonical (Hsp110 and Grp170) members. These two main Hsp70 groups are delineated from each other by distinct structural and functional specifications. Non-canonical Hsp70s are considered as holdase chaperones, while canonical Hsp70s are refoldases. This unique characteristic feature is mirrored by the distinct structural features of these two groups of chaperones. Hsp110/Grp170 members are larger as they possess an extended acidic insertion in their substrate binding domains. While the role of canonical Hsp70s in cancer has received a fair share of attention, the roles of non-canonical Hsp70s in cancer development has received less attention in comparison. In the current review, we discuss the structure-function features of non-canonical Hsp70s members and how these features impact their role in cancer development. We further mapped out their interactome and discussed the prospects of targeting these proteins in cancer therapy.

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“…Accordingly, Li et al were the first researchers to exhibit cell surface GRP94 expression through immunofluorescence staining from nonpermeabilized SK-BR-3 human breast cancer cells [ 157 ]. Over the following years, reports have shown that cell surface GRP94 is highly expressed in various human cancer cell lines, such as SLR21 renal cancer, PANC10.05 pancreatic cancer, OVCAR3 ovarian cancer, DU-145 prostate cancer, WM1158 melanoma, and HCT-116 colorectal cancer cells [ 110 , 158 , 159 ]. Moreover, Melendez et al demonstrated that cell surface GRP94 is especially expressed in MCF-7 and AU565 malignant breast cancer cells and not in MCF-10A and HMEC nonmalignant breast cancer cells [ 160 ].…”

Section: The Development Of Grp94-specific Inhibitorsmentioning

confidence: 99%

“…Moreover, a study by Hou et al reported that GRP94-targeting mouse mAb blocks the interaction between GRP94 and estrogen receptor-α36 (ER-α36) in the plasma membrane of MDA-MB-231 breast cancer cells, which play an important role in breast cancer growth and development. The same study showed that antibody treatment significantly inhibits breast cancer cell growth and invasion in vitro as well as tumor growth in a mouse xenograft model [ 159 ]. Another study also found that GRP94 mouse mAb specifically blocks the GRP94–uPAR interaction and inhibits uPAR-driven liver cancer cell growth, survival, and invasion, both in vitro and in vivo [ 161 ].…”

Section: The Development Of Grp94-specific Inhibitorsmentioning

confidence: 99%

Cell Surface GRP94 as a Novel Emerging Therapeutic Target for Monoclonal Antibody Cancer Therapy

Kim

Cho

Lee

2021

Cells

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Glucose-regulated protein 94 (GRP94) is an endoplasmic reticulum (ER)-resident member of the heat shock protein 90 (HSP90) family. In physiological conditions, it plays a vital role in regulating biological functions, including chaperoning cellular proteins in the ER lumen, maintaining calcium homeostasis, and modulating immune system function. Recently, several reports have shown the functional role and clinical relevance of GRP94 overexpression in the progression and metastasis of several cancers. Therefore, the current review highlights GRP94’s physiological and pathophysiological roles in normal and cancer cells. Additionally, the unmet medical needs of small chemical inhibitors and the current development status of monoclonal antibodies specifically targeting GRP94 will be discussed to emphasize the importance of cell surface GRP94 as an emerging therapeutic target in monoclonal antibody therapy for cancer.

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Molecular Stressors Engender Protein Connectivity Dysfunction through Aberrant N-Glycosylation of a Chaperone

Cited by 37 publications

References 86 publications

Molecular Chaperone GRP94/GP96 in Cancers: Oncogenesis and Therapeutic Target

Molecular Chaperone GRP94/GP96 in Cancers: Oncogenesis and Therapeutic Target

The Role of Non-Canonical Hsp70s (Hsp110/Grp170) in Cancer

Cell Surface GRP94 as a Novel Emerging Therapeutic Target for Monoclonal Antibody Cancer Therapy

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