IGFBP3 and BAG1 enhance radiation-induced apoptosis in squamous esophageal cancer cells

Yoshino, Kei; Motoyama, Satoru; Koyota, Souichi; Shibuya, Kaori; Usami, Shuetsu; Maruyama, Kiyotomi; Saito, Hajime; Minamiya, Yoshihiro; Sugiyama, Toshihiro; Ogawa, Jun–ichi

doi:10.1016/j.bbrc.2010.12.115

Cited by 26 publications

(25 citation statements)

References 41 publications

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“…Cell cycle distribution between the two cell lines does not differ, but the IGFBP-3-expressing cells show a marked increase in apoptosis. Other studies have similarly shown an enhanced apoptotic response to radiation in the presence of increased IGFBP-3 (Hollowood et al, 2000; Yoshino et al, 2011). IGFBP-3 is reported to be more highly expressed in radiosensitive than radioresistant cell lines (Achary et al, 2000; Zhao et al, 2012), and IGFBP-3 downregulation can reduce radiosensitivity (Yoshino et al, 2011).…”

Section: Role Of Igfbp-3 In the Dna Damage Responsementioning

confidence: 74%

Nuclear actions of insulin-like growth factor binding protein-3

Baxter

2015

Gene

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In addition to its actions outside the cell, cellular uptake and nuclear import of insulin-like growth factor binding protein-3 (IGFBP-3) has been recognized for almost two decades, but knowledge of its nuclear actions has been slow to emerge. IGFBP-3 has a functional nuclear localization signal and interacts with the nuclear transport protein importin-β. Within the nucleus IGFBP-3 appears to have a role in transcriptional regulation. It can bind to the nuclear receptor, retinoid X receptor-α and several of its dimerization partners, including retinoic acid receptor, vitamin D receptor (VDR), and peroxisome proliferator-activated receptor-γ (PPARγ). These interactions modulate the functions of these receptors, for example inhibiting VDR-dependent transcription in osteoblasts and PPARγ-dependent transcription in adipocytes. Nuclear IGFBP-3 can be detected by immunohistochemistry in cancer and other tissues, and its presence in the nucleus has been shown in many cell culture studies to be necessary for its pro-apoptotic effect, which may also involve interaction with the nuclear receptor Nur77, and export from the nucleus. IGFBP-3 is p53-inducible and in response to DNA damage, forms a complex with the epidermal growth factor receptor (EGFR), translocating to the nucleus to interact with DNA-dependent protein kinase. Inhibition of EGFR kinase activity or downregulation of IGFBP-3 can inhibit DNA double strand-break repair by nonhomologous endjoining. IGFBP-3 thus has the ability to influence many cell functions through its interactions with intranuclear pathways, but the importance of these interactions in vivo, and their potential to be targeted for therapeutic benefit, require further investigation.

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Section: Role Of Igfbp-3 In the Dna Damage Responsementioning

confidence: 74%

Nuclear actions of insulin-like growth factor binding protein-3

Baxter

2015

Gene

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“…Thus, identification of reliable markers of radiosensitivity and key molecules that mediate susceptibility to radiotherapy in esophageal cancer would be highly desirable [3]. The human regenerating gene (REG) I was originally isolated as an endogenous growth factor from pancreatic islet β cells [4,5].…”

Section: Introductionmentioning

confidence: 99%

REG Iα activates c-Jun through MAPK pathways to enhance the radiosensitivity of squamous esophageal cancer cells

et al. 2015

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Identification of the key molecules that mediate susceptibility to anticancer treatments would be highly desirable. Based on clinical and cell biological studies, we recently proposed that regenerating gene (REG) Iα may be such a molecule. In the present study, we hypothesized that REG Iα increases radiosensitivity through activation of mitogen-activated protein kinase (MAPK) pathways. To test that idea, we transfected TE-5 and TE-9 squamous esophageal cancer cells with REG Iα and examined its involvement in MAPK signaling and its effect on susceptibility to radiotherapy. We found that REG Iα-expressing cells showed increased expression of c-Jun messenger RNA (mRNA) and phospho-c-Jun protein mediated via the c-Jun N-terminal kinase (JNK) pathway and extracellular signal-regulated kinase (ERK) pathway, as well as increased radiosensitivity. Immunohistochemical analysis confirmed the activation of c-Jun in tumors expressing REG Iα. Collectively, these findings suggest that REG Iα activates c-Jun via the JNK and ERK pathway, thereby enhancing radiosensitivity.

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“…IGFBP-3 can directly mediate or accentuate apoptotic cell death by DNAdamage-associated agents such as ceramide (Gill et al 1997), UV radiation (Hollowood et al 2000), paclitaxel (Fowler et al 2000), etoposide (Drivdahl et al 2001;Lin et al 2014) and doxorubicin (Granata et al 2003). IGFBP-3 upregulation was shown to be associated with radiosensitive, compared to radioresistant, cervical cancer cell lines (Achary et al 2000), and a similar observation has been reported in esophageal cancer cells (Yoshino et al 2011). Similarly, increased expression of IGFBP-3 was associated with enhanced sensitivity to the cytotoxic effects of cisplatin in esophageal cancer, and this was reversed by silencing of IGFBP-3 (Zhao et al 2012).…”

Section: Igfbps and The Dna Damage Responsementioning

confidence: 76%

Involvement of the insulin-like growth factor binding proteins in the cancer cell response to DNA damage

Chua

Lin

Martin

et al. 2015

J. Cell Commun. Signal.

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The complex mechanisms that cells have evolved to meet the challenge of constant exposure to DNA‐damaging stimuli, also serve to protect cancer cells from the cytotoxic effects of chemo‐ and radiotherapy. IGFBPs appear to be involved, directly or indirectly, in some of these protective mechanisms. Activation of p53 is an early response to genotoxic stress, and all six human IGFBP genes have predicted p53 response elements in their promoter and/or intronic regions, at least some of which are functional. IGFBP3 has been extensively characterized as a p53‐inducible gene, but in some cases it is suppressed by mutant p53 forms. DNA double‐strand breaks (DSBs), induced by radiotherapy and some chemotherapies, potentially lead to apoptotic cell death, senescence, or repair and recovery. DSB damage can be repaired by homologous recombination or non‐homologous end‐joining (NHEJ), depending on the cell cycle stage, availability of key repair proteins, and other factors. The epidermal growth factor receptor (EGFR) has been implicated in the NHEJ pathway, and EGFR inhibition may inhibit repair, promoting apoptosis and thus improving sensitivity to chemotherapy or radiotherapy. Both IGFBP‐3 and IGFBP‐6 interact with components of the NHEJ pathway, and IGFBP‐3 can facilitate this process through direct interaction with both EGFR and the catalytic subunit of DNA‐PK. Cell fate after DNA damage may in part be regulated by the balance between the sphingolipids ceramide and sphingosine‐1‐phosphate, and IGFBPs can influence the production of both lipids. A better understanding of the involvement of IGFBPs in the DNA damage response in cancer cells may lead to improved methods of sensitizing cancers to DNA‐damaging therapies.

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IGFBP3 and BAG1 enhance radiation-induced apoptosis in squamous esophageal cancer cells

Cited by 26 publications

References 41 publications

Nuclear actions of insulin-like growth factor binding protein-3

Nuclear actions of insulin-like growth factor binding protein-3

REG Iα activates c-Jun through MAPK pathways to enhance the radiosensitivity of squamous esophageal cancer cells

Involvement of the insulin-like growth factor binding proteins in the cancer cell response to DNA damage

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