Grp94-specific monoclonal antibody to counteract BRAF inhibitor resistance in BRAFV600E melanoma

Sabbatino, Francesco; Favoino, Elvira; Wang, Yun; Wang, X; Villani, Vincenzo; Cai, Li; Yang, Li; Ferrone, Soldano; Ferrone, Christine

doi:10.1186/1479-5876-13-s1-k12

Cited by 14 publications

(12 citation statements)

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“…Cells were collected and washed twice with PBS before being stained. Cells were incubated with primary antibodies respectively including mouse antihuman CRT antibody TO-11 [36] and human antihuman HSP90 antibody (W9 which recognizes an epitope of an isoform of HSP90, GRP94 selectively expressed on cancer cell surface [37]) at 4°C for 1 h, then incubated respectively with Allophycocyanin (APC) AffiniPure F (ab') 2 Fragment Goat Anti-Mouse IgG (H + L) or R-Phycoerythrin AffiniPure F (ab') 2 Fragment Goat Anti-Human IgG, Fcγ fragment from Jackson ImmunoResearch Laboratories, Inc. USA. Isotype-matched IgG antibodies were used as controls.…”

Section: Flow Cytometric Analyses For Apoptotic Cells Cell Surface Ementioning

confidence: 99%

Induction of immunogenic cell death in radiation-resistant breast cancer stem cells by repurposing anti-alcoholism drug disulfiram

Sun

Yang

Toprani³

et al. 2020

Cell Commun Signal

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Background: The current successful clinical use of agents promoting robust anti-tumor immunity in cancer patients warrants noting that radiation therapy (RT) induces immunogenic cell death (ICD) of tumor cells, which can generate anti-tumor immune responses. However, breast cancer stem cells (BCSCs) are resistant to RT and RT alone usually failed to mount an anti-tumor immune response. Methods: High aldehyde dehydrogenase activity (ALDH) bright and CD44 + /CD24 − /ESA + cancer cells, previously shown to have BCSC properties, were isolated from human MDA-MB-231 and UACC-812 breast cancer cell lines by flow cytometer. Flow sorted BCSCs and non-BCSCs were further tested for their characteristic of stemness by mammosphere formation assay. Induction of ICD in BCSCs vs. non-BCSCs in response to different in vitro treatments was determined by assessing cell apoptosis and a panel of damage-associated molecular pattern molecules (DAMPs) by flow and enzyme-linked immunosorbent assay (ELISA). Results: We found that ionizing radiation (IR) triggered a lower level of ICD in BCSCs than non-BCSCs. We then investigated the ability of disulfiram/cooper (DSF/Cu) which is known to preferentially induce cancer stem cells (CSCs) apoptosis to enhance IR-induced ICD of BCSCs. The results indicate that DSF/Cu induced a similar extent of IDC in both BCSCs and non-BCSCs and rendered IR-resistant BCSCs as sensitive as non-BCSCs to IR-induced ICD. IR and DSF/Cu induced ICD of BCSCs could be partly reversed by pre-treatment of BCSCs with a reactive oxygen species (ROS) scavenger and XBP1s inhibitors. Conclusion: DSF/Cu rendered IR-resistant BCSCs as sensitive as non-BCSCs to IR-induced ICD. Our data demonstrate the potential of IR and DSF/Cu to induce ICD in BCSCs and non-BCSCs leading to robust immune responses against not only differentiated/differentiating breast cancer cells but also BCSCs, the root cause of cancer formation, progression and metastasis.

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Section: Flow Cytometric Analyses For Apoptotic Cells Cell Surface Ementioning

confidence: 99%

Induction of immunogenic cell death in radiation-resistant breast cancer stem cells by repurposing anti-alcoholism drug disulfiram

Sun

Yang

Toprani³

et al. 2020

Cell Commun Signal

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“…Specific monoclonal antibodies against GRP94 were used as powerful tools to inhibit cancer growth and development in tumor tissues. For instance, the monoclonal antibody (W9 mAb) was recently used and precisely targets the extracellular epitope of gp96 which is barely found in normal cells [ 232 ]. Another study used GRP94 or gp96 monoclonal antibody (gp96 mAb) to interrupt the HER2 dimerization and phosphorylation in breast cancer, which lead ultimately to inhibiting their growth and proliferation both in vitro and in vivo [ 215 ].…”

Section: Role Of Hsp90 Isoforms In Pathological Conditionsmentioning

confidence: 99%

The HSP90 Family: Structure, Regulation, Function, and Implications in Health and Disease

Hoter

El-Sabban

Naim³

2018

IJMS

442

363

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The mammalian HSP90 family of proteins is a cluster of highly conserved molecules that are involved in myriad cellular processes. Their distribution in various cellular compartments underlines their essential roles in cellular homeostasis. HSP90 and its co-chaperones orchestrate crucial physiological processes such as cell survival, cell cycle control, hormone signaling, and apoptosis. Conversely, HSP90, and its secreted forms, contribute to the development and progress of serious pathologies, including cancer and neurodegenerative diseases. Therefore, targeting HSP90 is an attractive strategy for the treatment of neoplasms and other diseases. This manuscript will review the general structure, regulation and function of HSP90 family and their potential role in pathophysiology.

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“…Sabbatino et al recently developed a novel monoclonal antibody (W9 mAb), which selectively targets the extracellular epitope of gp96 that is not detectable on normal cells but highly expressed on malignant cells. Further work demonstrated that W9 mAb can increase and restore sensitivity of human B-RAF V600E melanoma cells to B-RAF inhibitors [109]. A different study also demonstrated use of another monoclonal antibody, gp96 monoclonal antibody (gp96 mAb), to interfere with gp96-dependent HER2 dimerization and phosphorylation in breast cancer, and to induce anti-proliferative effects in HER2-driven cell growth both in vitro and in vivo [110].…”

Section: Role Of Gp96 In Cancermentioning

confidence: 99%

Clients and Oncogenic Roles of Molecular Chaperone gp96/grp94

Ansa-Addo¹,

Thaxton²,

Hong³

et al. 2016

CTMC

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As an endoplasmic reticulum heat shock protein (HSP) 90 paralogue, glycoprotein (gp) 96 possesses immunological properties by chaperoning antigenic peptides for activation of T cells. Genetic studies in the last decade have unveiled that gp96 is also an essential master chaperone for multiple receptors and secreting proteins including Toll-like receptors (TLRs), integrins, the Wnt co-receptor, Low Density Lipoprotein Receptor-Related Protein 6 (LRP6), the latent TGFβ docking receptor, Glycoprotein A Repetitions Predominant (GARP), Glycoprotein (GP) Ib and insulin-like growth factors (IGF). Clinically, elevated expression of gp96 in a variety of cancers correlates with the advanced stage and poor survival of cancer patients. Recent preclinical studies have also uncovered that gp96 expression is closely linked to cancer progression in multiple myeloma, hepatocellular carcinoma, breast cancer and inflammation-associated colon cancer. Thus, gp96 is an attractive therapeutic target for cancer treatment. The chaperone function of gp96 depends on its ATPase domain, which is structurally distinct from other HSP90 members, and thus favors the design of highly selective gp96-targeted inhibitors against cancer. We herein discuss the strategically important oncogenic clients of gp96 and their underlying biology. The roles of cell-intrinsic gp96 in T cell biology are also discussed, in part because it offers another opportunity of cancer therapy by manipulating levels of gp96 in T cells to enhance host immune defense.

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Grp94-specific monoclonal antibody to counteract BRAF inhibitor resistance in BRAFV600E melanoma

Cited by 14 publications

References 0 publications

Induction of immunogenic cell death in radiation-resistant breast cancer stem cells by repurposing anti-alcoholism drug disulfiram

Induction of immunogenic cell death in radiation-resistant breast cancer stem cells by repurposing anti-alcoholism drug disulfiram

The HSP90 Family: Structure, Regulation, Function, and Implications in Health and Disease

Clients and Oncogenic Roles of Molecular Chaperone gp96/grp94

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