Down‐regulation of BiP/GRP78 sensitizes resistant prostate cancer cells to gene‐therapeutic overexpression of REIC/Dkk‐3

Tanimoto, Ryuta; Sakaguchi, Masakiyo; Abarzúa, Fernando; Kataoka, Ken; Kurose, Kaoru; Murata, Hitoshi; Nasu, Yasutomo; Kumon, Hiromi; Huh, Nam

doi:10.1002/ijc.24764

Cited by 20 publications

(13 citation statements)

References 22 publications

(31 reference statements)

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“…The glucose-regulated protein, Hspa5, belongs to the Hsp70 protein family, which is involved in a number of cellular processes that maintain the homeostasis of cells. It is strongly induced in tumors and plays critical roles in the stress of oncogenesis (15)(16)(17)(18). We previously showed that the overexpression of Hsp70-2 protected cancer cells against apoptosis induced by hypoxia and that the upregulated expression of Hspa5 protected NIT-1 cells from death induced by streptozotocin, cytokines or cytotoxic T lymphocytes (19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

Co-silencing of Birc5 (survivin) and Hspa5 (Grp78) induces apoptosis in hepatoma cells more efficiently than single gene interference

Wang

Shu

et al. 2012

International Journal of Oncology

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Birc5 (previously known as survivin) is a cancer-specific protein. Due to the upregulation of its expression in various human malignancies and its key role in apoptosis, proliferation and angiogenesis, Birc5 has attracted attention as a target for anticancer therapies. In this study, when Birc5 was silenced in HepG2 cells, 29.7±3.3% cells underwent apoptosis as expected. It was found that the expression levels of glucose-regulated protein 78 (Hspa5, previously known as Grp78) was increased by almost 3-fold in Birc5-silenced HepG2 cells. Hspa5, a master regulator of the anti-apoptotic unfolded protein response signalling network, can also promote tumor proliferation, survival and metastasis. Hence, we hypothesized that the co-silencing of Birc5 and Hspa5 may exert a stronger apoptosis-inducing effect than single gene interference. To verify this, the expression levels of Birc5 and Hspa5 in human hepatocellular carcinoma tissues were determined. Immunohistochemical staining showed that the expression of Birc5 and Hspa5 was elevated in 28 out of 31 samples. Additionally, plasmid-based siRNA against Birc5 and/or Hspa5 were constructed and transfected into the human hepatocellular liver carcinoma cell line, HepG2. Compared with the HepG2 cells, in which Birc5 or Hspa5 were silenced alone, only 44.2±3.4% of the co-silenced cells proliferated, and 40.3±3.7% co-silenced cells underwent apoptosis (p<0.05). Furthermore, tumor formation from inoculated subcutaneous co-silenced cells in nude mice was inhibited significantly. The current study suggests that Birc5 and Hspa5 could be important survival factors for hepatoma carcinoma cells and that the simultaneous knockdown of Birc5 and Hspa5 is more effective in inducing apoptosis in HepG2 cells than the knockdown of Birc5 or Hspa5 alone. The co-silencing of Birc5 and Hspa5 could be warranted for cancer therapy.

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Section: Introductionmentioning

confidence: 99%

Co-silencing of Birc5 (survivin) and Hspa5 (Grp78) induces apoptosis in hepatoma cells more efficiently than single gene interference

Wang

Shu

et al. 2012

International Journal of Oncology

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“…A study utilizing the gastrocnemius muscle of mdx and wild‐type mice found elevated levels of stress‐related chaperone proteins such as GRP78 . This is potentially a very interesting finding as GRP78 (also known as BiP) levels have already been altered as therapeutic intervention in other diseases such as cancer and photoreceptor degeneration . In this study, around 9.3% of 789 detected proteins were significantly altered.…”

Section: Resultsmentioning

confidence: 53%

Mass spectrometry‐based protein analysis to unravel the tissue pathophysiology in Duchenne muscular dystrophy

Carr

Zahedi

Lochmüller

et al. 2017

Proteomics Clinical Apps

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Duchenne muscular dystrophy (DMD) is a genetic muscle wasting condition with limited treatment options available and is caused by the lack of dystrophin. However, pathophysiology of different tissues is variable showing different histological and molecular signatures. Recently, a number of studies have employed gel-free proteomic approaches to unveil the molecular pathophysiology in terms of tissue-specific proteome changes in dystrophin deficiency. The authors analyzed studies in models of dystrophin deficiency and patients both from the published literature. The authors created a database containing all of the significantly differentially expressed proteins. By the integration of data from nine studies, the authors have identified 31 proteins which are commonly affected in different tissues by dystrophin deficiency. These proteins represent pathways involved in the maintenance of the actin cytoskeleton and those involved in cellular energy metabolism among others. Also represented is glyceraldehyde-3-phosphate dehydrogenase (GAPDH), often used as a loading control in protein assays, it appears to be highly variable, and should be replaced by other controls. The same intersection of data was performed using studies of the blood and urine of Duchenne muscular dystrophy patients and/or animal models and identified 33 proteins that are commonly differentially expressed. These proteins may themselves be novel therapeutic targets biomarkers that could monitor disease progression.

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“…We also reported that resistant clones isolated from sesitive PC3 prostate cancer cells expressed BiP/Grp78, an ER-resisting chaperone protein, at enhanced levels (20). Downregulation of BiP/Grp78 with specific siRNA sensitized the resistant clones to Ad-REIC.…”

Section: Discussionmentioning

confidence: 85%

Partial sensitization of human bladder cancer cells to a gene-therapeutic adenovirus carrying REIC/Dkk-3 by downregulation of BRPK/PINK1

Jin

Murata²,

Sakaguchi³

et al. 2011

Oncol Rep

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Abstract. REIC/Dkk-3 is a tumor suppressor gene that was first identified as a gene downregulated in association with immortalization of normal human fibroblasts. We have demonstrated that an adenovirus carrying REIC/Dkk-3 (Ad-REIC) showed a tumor-specific killing effect on a wide range of cancers. However, some human cancers, bladder cancers in particular, are resistant to Ad-REIC. In this study, we investigated the combination effect of downregulation of BRPK/PINK1 (PINK1) and Ad-REIC on bladder cancer cells. Five bladder cancer cell lines among six cell lines examined were resistant to Ad-REIC. Among the cell lines, the resistance of two cell lines was probably due to low infection efficiency of the adenovirus. PINK1-specific siRNA remarkably downregulated Bcl-x L and TRAP1 proteins and upregulated BAX protein expression. Finally, downregulation of PINK1 partially sensitized the other three cell lines that were resistant to Ad-REIC. This sensitization was associated with increasing production of reactive oxygen species (ROS). These results indicate that PINK1 is one of the key molecules for the mitochondrial protection system and that PINK1 can be a new target molecule to sensitize bladder cancer cells that are resistant to Ad-REIC.

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Down‐regulation of BiP/GRP78 sensitizes resistant prostate cancer cells to gene‐therapeutic overexpression of REIC/Dkk‐3

Cited by 20 publications

References 22 publications

Co-silencing of Birc5 (survivin) and Hspa5 (Grp78) induces apoptosis in hepatoma cells more efficiently than single gene interference

Co-silencing of Birc5 (survivin) and Hspa5 (Grp78) induces apoptosis in hepatoma cells more efficiently than single gene interference

Mass spectrometry‐based protein analysis to unravel the tissue pathophysiology in Duchenne muscular dystrophy

Partial sensitization of human bladder cancer cells to a gene-therapeutic adenovirus carrying REIC/Dkk-3 by downregulation of BRPK/PINK1

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