Glucose-Regulated Protein 94 (GRP94): A Novel Regulator of Insulin-Like Growth Factor Production

Argon, Yair; Marzec, Michał; Grimberg, Adda

doi:10.3390/cells9081844

Cited by 19 publications

(9 citation statements)

References 90 publications

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“…Moreover, GRP94 is responsible for chaperoning multiple proteins that have been reported to play essential roles in immune response and promoting cancer development, including Toll-like receptors (TLRs) (5)(6)(7)(8), the majority of a and b integrin subunits (7,9), Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6) (9, 10), glycoprotein A repetitions predominant (GARP) (11)(12)(13)(14)(15), Insulin-like growth factor (IGF) (16)(17)(18), as well as platelet glycoprotein Ib-IX-V complex (19) (Figure 1A).…”

Section: Introductionmentioning

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: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…The milk protein-derived amino acids tryptophan, methionine, and arginine synergistically enhance hepatic IGF-1 synthesis and secretion [212,[246][247][248][249][250][251][252] . Exposure to bovine MEX to cultured human colonic LS174T cells enhanced the expression of glucose-regulated protein 94 (GRP94) [253] , the most abundant intraluminal endoplasmic reticulum chaperone that aids in the synthesis of IGF-1, IGF-2, and proinsulin [254,255] .…”

Section: Insulin-like Growth Factormentioning

confidence: 99%

“…In fact, increasing evidence presented by studies in humans and animal models supports the view that MEX and their miRs are bioavailable, reach the systemic circulation [420,422,[434][435][436][437] , and modify gene expression of the milk recipient [359,418,[437][438][439] . It has been demonstrated that bovine MEX increased the expression of GRP94 [253] , which is a key endoplasmic reticulum chaperone enhancing the synthesis of insulin, IGF-1, and IGF-2 [254,255,440] . Of note, co-downregulation of GRP78 and GRP94 expression induced apoptosis and inhibited migration in PC3 cells [441] .…”

Section: Milk Exosomal Micrornasmentioning

confidence: 99%

“…Of note, co-downregulation of GRP78 and GRP94 expression induced apoptosis and inhibited migration in PC3 cells [441] . MEX miR-mediated changes of epigenetic regulation appear to be beneficial for growth and maturation of the infant [253,432,[442][443][444][445][446][447][448][449] , but it may exert adverse health effects during long-term exposure associated with persistent overactivation of mTORC1 [450] .…”

Section: Milk Exosomal Micrornasmentioning

confidence: 99%

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The endocrine and epigenetic impact of persistent cow milk consumption on prostate carcinogenesis

Melnik¹,

John²,

Weiskirchen³

et al. 2022

jtgg

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This review analyzes the potential impact of milk-induced signal transduction on the pathogenesis of prostate cancer (PCa). Articles in PubMed until November 2021 reporting on milk intake and PCa were reviewed. Epidemiological studies identified commercial cow milk consumption as a potential risk factor of PCa. The potential impact of cow milk consumption on the pathogenesis of PCa may already begin during fetal and pubertal prostate growth, critical windows with increased vulnerability. Milk is a promotor of growth and anabolism via activating insulin-like growth factor-1 (IGF-1)/phosphatidylinositol-3 kinase (PI3K)/AKT/mechanistic target of rapamycin complex 1 (mTORC1) signaling. Estrogens, major steroid hormone components of commercial milk of persistently pregnant dairy cows, activate IGF-1 and mTORC1. Milk-derived signaling synergizes with common driver mutations of the PI3K/AKT/mTORC1 signaling pathway that intersect with androgen receptor, MFG-E8, MAPK, RUNX2, MDM4, TP53, and WNT signaling, respectively. Potential exogenously induced drivers of PCa are milk-induced elevations of growth hormone, IGF-1, MFG-E8, estrogens, phytanic acid, and aflatoxins, as well as milk exosome-derived oncogenic microRNAs including miR-148a, miR-21, and miR-29b. Commercial cow milk intake, especially the consumption of pasteurized milk, which represents the closest replica of native milk, activates PI3K-AKT-mTORC1 signaling via cow milk’s endocrine and epigenetic modes of action. Vulnerable periods for adverse nutrigenomic impacts on prostate health appear to be the fetal and pubertal growth periods, potentially priming the initiation of PCa. Cow milk-mediated overactivation of PI3K-AKT-mTORC1 signaling synergizes with the most common genetic deviations in PCa, promoting PCa initiation, progression, and early recurrence.

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“…Tumors often require hyperactivity of the IGF system as a means of progressing the neoplastic process. Over-expression of autocrine/paracrine IGF by tumor cells or supporting stromal cells serves to stimulate cancer progression [13,14].…”

Section: Morphological Examination Of the Peritoneummentioning

confidence: 99%

Relationship between comorbid pathology and tumor progression. Morphological portrayal of internal organs in modeling the growth of Guerin’s carcinoma under diabetic conditions

Shikhlyarova¹,

Frantsiyants²,

Kaplieva³

et al. 2022

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Topicality. An increase in the incidence of malignant tumors progressing against the background of various comorbid pathologies determines the need to study the mutual influence of pathological processes using experimental modeling. Such models, for example, can reproduce the tumor growth modified by the comorbid condition of diabetes mellitus, the incidence rate of which is now increasing exponentially. In this case, a clear demonstration of changes in the structure of organs outside the zone of the primary tumor node, using data on the direct growth of the tumor and the content of diabetes markers therein and in the perifocal zone, can serve as an evidence-based argument for the implementation of the mechanism of modified tumor progression. The aim of our research work is to assess the state of the histological structure of some internal organs (the kidneys, the ovaries, the peritoneum) when modeling the main pathological process in animals, the growth of Guerin’s carcinoma, against the background of a comorbid state of experimental diabetes. Materials and methods. We used 32 outbred male and female rats weighing 180-220 g to reproduce the model of experimental diabetes by a single intraperitoneal injection of alloxan at a dosage of 150 mg/kg of body weight. One week after the production of persistent hyperglycemia in the range of 25.4±1.2 mmol/l, the animals were transplanted with Guerin’s carcinoma subcutaneously in the region of the right shoulder blade. Upon expiration of 2 weeks, the animals were decapitated, and the harvested organs were prepared according to the practice stages of morphological preparation for staining sections with hematoxylin-eosin, followed by morphological examination of the structure with the use of the Leica DM LS2 microscope with the Olympus optical. C-5050 Zoom video camera and the Morfotest software. Photographing was carried out with magnification x10, x40, x100. Results. Our study of the morphological portrayal of the ovary, the kidney, the visceral and parietal peritoneum bears witness to the identity of the changes, consisting in a total metastatic lesion and abnormal transformation of the normal structure of all the studied organs only in the female rats, when modeling the comorbid state of diabetes mellitus. At the same time, the aggressive nature of the tumor progression was manifested in the blood filling of the vessels and hemorrhage, followed by the release of tumor cells, their settlement, the enhanced proliferation, the formation of strands and compaction of cell aggregations throughout the volume of the organ. Some gender specific features of the tumor progression were noted, which were found in the female rats along the path of active metastasizing in case of small primary tumors, and in the male rats along the path of stimulating the growth of the primary focus without metastasizing. It was revealed that these differences are associated with different degrees of saturation of the tumor and perifocal zone with glucose, and they are determined by the state of the insulin/insulin-like growth factor (IGF) axis. Conclusion. Morphological examination of the organs affected by metastatic Guerin’s carcinoma in the female rats with diabetes mellitus makes it possible to detect not only the synergy of both pathological processes, but also a powerful pro-oncogenic effect of the comorbid state of diabetes in the implementation of the tumor growth program.

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Glucose-Regulated Protein 94 (GRP94): A Novel Regulator of Insulin-Like Growth Factor Production

Cited by 19 publications

References 90 publications

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

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

The endocrine and epigenetic impact of persistent cow milk consumption on prostate carcinogenesis

Relationship between comorbid pathology and tumor progression. Morphological portrayal of internal organs in modeling the growth of Guerin’s carcinoma under diabetic conditions

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