Mechanistic Studies of a Peptidic GRP78 Ligand for Cancer Cell-Specific Drug Delivery

Liu, Ying; Steiniger, Sebastian C.J.; Kim, Young Soo; Kaufmann, Gunnar F.; Felding-Habermann, Brunhilde; Janda, Kim D.

doi:10.1021/mp060122j

Cited by 108 publications

(116 citation statements)

References 39 publications

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“…58 Others found that members of the HSP70 family (including GRP78) on mammalian cells interact with scavenger molecules, which are responsible for the uptake of oxLDL, and lead to a rapid internalization of HSP70 antigens. 59 GRP78 is highly involved in the quality control of LDL receptors, and it associates with apolipoprotein B as part of a complex with other chaperones like GRP94, calreticulin and Erp72.…”

Section: Discussionmentioning

confidence: 99%

A new tumor-specific variant of GRP78 as target for antibody-based therapy

Rauschert

Brändlein

Holzinger

et al. 2008

Laboratory Investigation

121

104

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The chaperone GRP78 is a member of the heat-shock protein 70 (HSP70) family and is responsible for cellular homeostasis by preventing stress-induced apoptosis. GRP78 is expressed in all cells of the body. In malignant cells, which are permanently exposed to environmental stress, GRP78 is overexpressed and increased levels can be found in the cytoplasm and on the cell membrane. Thus, GRP78 promotes tumor proliferation, survival, metastases and resistance to a wide variety of therapies. Like other tumor-specific membrane molecules, GRP78 can also be present on cancer cells in a variant form. This modification qualifies it as a target for immune surveillance and antibody responses. The fully human monoclonal IgM antibody, SAM-6, was isolated from a gastric cancer patient and it binds to a new variant of GRP78 with a molecular weight of 82 kDa. The epitope is an O-linked carbohydrate moiety and is specific for malignant cells. These data show that cancer-specific modifications of cell-surface protection molecules are (a) subject of an immune response and (b) ideal targets for new therapeutical approaches.

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Section: Discussionmentioning

confidence: 99%

A new tumor-specific variant of GRP78 as target for antibody-based therapy

Rauschert

Brändlein

Holzinger

et al. 2008

Laboratory Investigation

121

104

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“…11 GRP78 has a major role in regulating intracellular protein trafficking, 12 apoptosis, 13,14 cell surface receptor-mediated endocytosis, 15 and in a variety of cells, as a cell surface protein that functions as a receptor. 16 As a cell surface protein, GRP78 binds a number of different ligands.…”

mentioning

confidence: 99%

“…23 For over a decade, investigations have explored the divergent functions of GRP78 in nonmelanocytic malignancies, and have begun to focus on targeting the protein for a variety of therapeutic applications. 15,30 GRP78 expression has been studied in a variety of cancer cell lines, including the breast, melanoma, and prostate. [31][32][33][34] Quantitative analysis of GRP78 shows elevated levels in hepatocellular carcinoma and gastric cancer relative to surrounding nontumor tissue.…”

mentioning

confidence: 99%

Patterns of GRP78 and MTJ1 expression in primary cutaneous malignant melanoma

et al. 2010

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Cell surface expression of glucose-regulated protein 78 (GRP78) occurs in several types of cancer; however, its role in the behavior of primary cutaneous melanoma is not well studied. The association of cell surface GRP78 with other proteins such as MTJ1 stimulates cell proliferation. In this study, we characterized the pattern of expression of GRP78 and MTJ1 in invasive primary cutaneous melanomas and analyzed the relationships between the pattern of expression and various clinicopathological parameters. We found two patterns of GRP78 expression in invasive primary cutaneous melanoma. One pattern showed a gradual fading of protein expression from superficial to deeper levels within the same tumor. The second pattern of expression showed a similar fading with an abrupt regaining of expression at the deep invasive edge of the melanoma. These two distinct patterns of GRP78 expression correlated with both patient survival and depth of tumor invasion. A moderate MTJ1 expression was found to be associated with decreased patient survival; however, no significant associations were observed between patterns of GRP78 and MTJ1 expression. Our study (1) describes two distinct patterns of GRP78 in invasive primary cutaneous melanoma, (2) inversely correlates regain of GRP78 expression with patient survival, and (3) suggests a modifying effect of MTJ1 on GRP78 in enhancing tumor aggressiveness.

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“…Such dissociation generates a potent transcription factor for UPR gene expression activating signaling pathways to maintain homeostasis (HOTAMISLIGIL, 2010;PFAFFENBACH;TODD;GLIMCHER, 2008). Induced HSPA5 has been used as possible activation markers of the antiapoptotic and antiproliferative agents in tumor cells creating a mechanism of resistance (KIM et al, 2006;LIU et al, 2007;MILOSZEWSKA et al, 2010;ROSATI et al, 2010;ROUE et al, 2011;TAN et al, 2011). On the other hand, the induction of anti-HSPA5 functions as an apoptotic protein, forming caspase 7 and 12 complexes, keeping them inactive and blocking their proapoptotic function (REDDY et al, 2003).…”

Section: Resultsmentioning

confidence: 99%

Homeostatic unbalance via HSPA5 gene expression in HepG2/C3A cells exposed to ?-tomatine

Mantovani

Brianese

Jacobs

et al. 2016

Semin. Cienc. Biol. Saude

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The α-tomatine is a glycoalkaloid found in immature tomatoes (Lycopersicon esculetum). Currently, α-tomatine has shown anticancer effects due to its anti-proliferative property. Stressors are one of the factors contributing to the antiproliferative activity of α-tomatine that can modify cellular homeostasis. Among the cell stressors are the endoplasmic reticulum stress response elements, which can be altered leading to cell death. In the course of this study, we verified the expression of genes involved in the stress response of the endoplasmic reticulum in HepG2/C3A cells. The α-tomatine reduced the viability of HepG2/C3A cells in a dose-dependent manner. Thus, we selected 2µg/mL of α-tomatine (62% in cell viability) to evaluate the gene expressions. After 24 hours of exposure to α-tomatine, the level of HSPA5 transcripts was reduced. The HSPA5 chaperone reduced marker is an indicative of homeostasis unbalance with the consequent lack of cellular resistance and, probably, cell death. Our results indicate the involvement of oxidative stress mechanisms in the death of HepG2/C3A cells exposed to α-tomatine Keywords: a-Tomatine. Antiproliferative. HSPA5 chaperone Resumoand show the effectiveness of the system as a future candidate for the cancer therapy studies.Palavras-chave: a-Tomatine. Antiproliferativo. HSPA5 chaperone A α-tomatina é um glicoalcaloide encontrado no tomate imaturo (Lycopersicon esculetum). Atualmente, a α-tomatina tem mostrado efeito anticancerígeno devido sua propriedade antiproliferativa. O estresse celular é um dos fatores que contribui para a atividade antiproliferative da α-tomatina que pode modificar a homeostase celular. Entre os estressores celulares esta os elementos de resposta ao estresse do retículo endoplasmático, que podem ser alterados, levando à morte celular. No decorrer deste estudo, verificamos que a expressão de genes envolvidos na resposta ao estresse do retículo endoplasmático em células HepG2/C3A. A α-tomatina reduziu a viabilidade das células HepG2/C3A de forma dose-dependente. Assim, selecionamos a concentração de 2µg/mL de α-tomatina (viabilidade celular de 62%) para avaliar a expressão gênica. Após 24 horas de exposição a α-tomatina, o nível de transcrição de HSPA5 foi reduzido. A redução de HSPA5 é um indicativo de desequilíbrio da homeostase, com a consequente falta de resistência celular e, provavelmente, a morte celular. Nossos resultados indicam o envolvimento de mecanismos de estresse oxidativo na morte de células HepG2/C3A exposto a α-tomatina e mostram a eficácia do sistema como um futuro candidato para os estudos de terapia de câncer.

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Mechanistic Studies of a Peptidic GRP78 Ligand for Cancer Cell-Specific Drug Delivery

Cited by 108 publications

References 39 publications

A new tumor-specific variant of GRP78 as target for antibody-based therapy

A new tumor-specific variant of GRP78 as target for antibody-based therapy

Patterns of GRP78 and MTJ1 expression in primary cutaneous malignant melanoma

Homeostatic unbalance via HSPA5 gene expression in HepG2/C3A cells exposed to ?-tomatine

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