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Subject Item: n2:23950876
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rdfs:seeAlso: n6:10.1371%2Fjournal.pone.0068784 n9:23950876 n10:0 n11:0
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Subject Item: _:vb24477680
rdf:type: n8:Section
dc:title: introduction
n8:contains: _:vb24477684 _:vb24477685 _:vb24477686 _:vb24477687 _:vb24477681 _:vb24477682 _:vb24477683 _:vb24477692 _:vb24477693 _:vb24477694 _:vb24477688 _:vb24477689 _:vb24477690 _:vb24477691

Subject Item: _:vb24477681
rdf:type: n4:Context
rdf:value: Prostate cancer (PC) is the most common malignancy and the second leading cause of cancer-related deaths among male patients [>>1<<]. During cancer progression, the initial growth of PC cells is androgen-dependent, and these cells undergo apoptosis upon androgen depletion.
n4:mentions: n2:20610543

Subject Item: _:vb24477682
rdf:type: n4:Context
rdf:value: As a consequence, androgen ablation was considered the standard treatment for PC for over 50 years [>>2<<]. Many patients eventually developed a hormone-refractory disease due to the growth of androgen-refractory cancer cells, which leads to failure of androgen ablation therapy and leaves patients with fewer therapeutic options [3], [4].
n4:mentions: n2:7512791

Subject Item: _:vb24477683
rdf:type: n4:Context
rdf:value: Many patients eventually developed a hormone-refractory disease due to the growth of androgen-refractory cancer cells, which leads to failure of androgen ablation therapy and leaves patients with fewer therapeutic options [>>3<<], [4]. Combination of definitive local therapies, such as radical prostatectomy together with adjuvant radiotherapy, has been demonstrated to improve the survival of PC patients [5], [6]. However, such therapy is challenged by the
n4:mentions: n2:16551847

Subject Item: _:vb24477684
rdf:type: n4:Context
rdf:value: Many patients eventually developed a hormone-refractory disease due to the growth of androgen-refractory cancer cells, which leads to failure of androgen ablation therapy and leaves patients with fewer therapeutic options [3], [>>4<<]. Combination of definitive local therapies, such as radical prostatectomy together with adjuvant radiotherapy, has been demonstrated to improve the survival of PC patients [5], [6]. However, such therapy is challenged by the emergence of
n4:mentions: n2:12878745

Subject Item: _:vb24477685
rdf:type: n4:Context
rdf:value: Combination of definitive local therapies, such as radical prostatectomy together with adjuvant radiotherapy, has been demonstrated to improve the survival of PC patients [>>5<<], [6]. However, such therapy is challenged by the emergence of resistance in tumor cells. It is, therefore, of paramount importance to develop novel therapeutic strategies to overcome radioresistance and improve radio-sensitivity by
n4:mentions: n2:18602742

Subject Item: _:vb24477686
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rdf:value: play critical roles in cancer development and progression through the regulation on cell proliferation, apoptosis, anchorage-independent growth, invasion, angiogenesis, cancer immunity and resistance to chemo- and/or radiotherapy [>>7<<]. These two receptors are frequently overexpressed in a variety of human cancers including PC [8], [9], [10], and therefore could be used as candidates for targeted cancer therapy.
n4:mentions: n2:19754359

Subject Item: _:vb24477687
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rdf:value: These two receptors are frequently overexpressed in a variety of human cancers including PC [>>8<<], [9], [10], and therefore could be used as candidates for targeted cancer therapy.
n4:mentions: n2:18006757

Subject Item: _:vb24477688
rdf:type: n4:Context
rdf:value: These two receptors are frequently overexpressed in a variety of human cancers including PC [8], [>>9<<], [10], and therefore could be used as candidates for targeted cancer therapy.
n4:mentions: n2:17349528

Subject Item: _:vb24477689
rdf:type: n4:Context
rdf:value: These two receptors are frequently overexpressed in a variety of human cancers including PC [8], [9], [>>10<<], and therefore could be used as candidates for targeted cancer therapy.
n4:mentions: n2:12019176

Subject Item: _:vb24477690
rdf:type: n4:Context
rdf:value: treatment of different human cancers, As expected however, the development of de novo resistance has been observed in clinic after long-term use of these medicines, suggesting the existence of bypass mechanisms within tumor cells [>>11<<]. Mechanistic studies on the cellular and molecular events revealed that extensive crosstalk between EGFR and IGF1R signaling occurs at multiple levels, and that blockage of EGFR signaling leads to enhanced responses to the IGF1R ligand,
n4:mentions: n2:17259558

Subject Item: _:vb24477691
rdf:type: n4:Context
rdf:value: studies on the cellular and molecular events revealed that extensive crosstalk between EGFR and IGF1R signaling occurs at multiple levels, and that blockage of EGFR signaling leads to enhanced responses to the IGF1R ligand, IGF [>>12<<], [13]. These data imply that targeting both receptors at the same time could provide better efficacy in cancer treatment and overcome tumor resistance to an individual inhibitor, while improving the sensitivity of individual inhibitors to
n4:mentions: n2:19034632

Subject Item: _:vb24477692
rdf:type: n4:Context
rdf:value: studies on the cellular and molecular events revealed that extensive crosstalk between EGFR and IGF1R signaling occurs at multiple levels, and that blockage of EGFR signaling leads to enhanced responses to the IGF1R ligand, IGF [12], [>>13<<]. These data imply that targeting both receptors at the same time could provide better efficacy in cancer treatment and overcome tumor resistance to an individual inhibitor, while improving the sensitivity of individual inhibitors to
n4:mentions: n2:9185705

Subject Item: _:vb24477693
rdf:type: n4:Context
rdf:value: Consistently, studies have shown that dual targeting of both receptors blocks their reciprocal hyperphosphorylation, inhibits the proliferation and induces apoptosis in multiple cancer cells including PC and colorectal cancer [>>14<<], [15].
n4:mentions: n2:18922904

Subject Item: _:vb24477694
rdf:type: n4:Context
rdf:value: Consistently, studies have shown that dual targeting of both receptors blocks their reciprocal hyperphosphorylation, inhibits the proliferation and induces apoptosis in multiple cancer cells including PC and colorectal cancer [14], [>>15<<].
n4:mentions: n2:17320820

Subject Item: _:vb24477695
rdf:type: n8:Section
dc:title: materials and methods
n8:contains: _:vb24477696 _:vb24477697 _:vb24477698 _:vb24477699

Subject Item: _:vb24477696
rdf:type: n4:Context
rdf:value: Cells were irradiated as described by Liu et al [>>16<<]. In some experiments, the cells were also transfected with IRS1 or non-silencing control (NSC) siRNAs (50 nM, Invitrogen, Shanghai, China) according to manufacturer's protocol.
n4:mentions: n2:18799330

Subject Item: _:vb24477697
rdf:type: n4:Context
rdf:value: To detect apoptotic rate in treated cells, the cells were stained with Annexin V and PI, and then subjected to flow cytometry as described [>>16<<]. The Annexin V-positive and PI-negative cells undergoing early apoptosis were counted as apoptotic cells. All experiments were conducted in duplicates and data shown are representative of three independent experiments.
n4:mentions: n2:18799330

Subject Item: _:vb24477698
rdf:type: n4:Context
rdf:value: Immunoprecipitation and Western-blot assay were performed as described by Liu et al [>>17<<]. The following antibodies were from Cell Signaling:
n4:mentions: n2:15833875

Subject Item: _:vb24477699
rdf:type: n4:Context
rdf:value: The quantitative in vitro homologous recombination (HR) assay was performed using the pDR-GFP recombination reporter system [>>19<<]. Briefly, the pDR-GFP plasmid expressing two nonfunctional GFP genes was stably transfected into DU145 cells.
n4:mentions: n2:10051570

Subject Item: _:vb24477700
rdf:type: n8:Section
dc:title: results
n8:contains: _:vb24477701 _:vb24477702 _:vb24477703 _:vb24477704 _:vb24477705 _:vb24477706

Subject Item: _:vb24477701
rdf:type: n4:Context
rdf:value: For this purpose, we used ARCaPM, the mesenchymal counterpart of ARCaPE developed by Graham et al [>>21<<]. Both cells lines exhibit minimal expression of androgen receptor [22]. Consistent with previous findings by Buck et al [14], combined treatment with EGFR and IGF1R inhibitors could not synergistically inhibit mesenchymal cell growth in
n4:mentions: n2:18381457

Subject Item: _:vb24477702
rdf:type: n4:Context
rdf:value: Both cells lines exhibit minimal expression of androgen receptor [>>22<<]. Consistent with previous findings by Buck et al [14], combined treatment with EGFR and IGF1R inhibitors could not synergistically inhibit mesenchymal cell growth in response to irradiation, as it did for epithelial growth (Figure 1A).
n4:mentions: n2:8986779

Subject Item: _:vb24477703
rdf:type: n4:Context
rdf:value: Consistent with previous findings by Buck et al [>>14<<], combined treatment with EGFR and IGF1R inhibitors could not synergistically inhibit mesenchymal cell growth in response to irradiation, as it did for epithelial growth (Figure 1A).
n4:mentions: n2:18922904

Subject Item: _:vb24477704
rdf:type: n4:Context
rdf:value: For this analysis, the nuclear extract from R503 cells was used as the positive control, as demonstrated by Yang et al [>>23<<]. In addition, expression of NHEJ-related DNA repair proteins, including DNA-PK, Ku70, Ku80 and XRCC4, were not affected by AG1024, Erlotinib or both in DU145 cells (Figure 2E), suggesting that inhibition of these two signaling pathways
n4:mentions: n2:15956778

Subject Item: _:vb24477705
rdf:type: n4:Context
rdf:value: Previous studies revealed extensive crosstalk between EGFR and IGF1R signaling pathway at multiple levels [>>14<<]. Our data above have demonstrated that co-inhibition of EGFR and IGF1R could additively radio-sensitize PC cells through the impairment of HRR DSB repair.
n4:mentions: n2:18922904

Subject Item: _:vb24477706
rdf:type: n4:Context
rdf:value: Our current data on AG1024 and Erlotinib regulating IRS1 phosphorylation/activation implicated the potential involvement of IRS1/Rad51-mediated HRR in response to γ irradiation in PC cells, as previous study also indicated [>>24<<]. Indeed, our data showed that IRS1 phosphorylation was induced by γ-irradiation with peak activation achieved at 4 h after γ-irradiation in DU145 and PC3 cells, while the peak of IRS1 phosphorylation was delayed to 8 h after γ-irradiation
n4:mentions: n2:14559999

Subject Item: _:vb24477707
rdf:type: n8:Section
dc:title: discussion
n8:contains: _:vb24477708 _:vb24477709 _:vb24477710 _:vb24477711 _:vb24477712 _:vb24477713 _:vb24477714

Subject Item: _:vb24477708
rdf:type: n4:Context
rdf:value: Without proper DNA repair capacity, cells undergo apoptosis, mitotic catastrophe, autophagy, cellular senescence, or even carcinogensis [>>25<<]. However, in tumor cells after radiation therapy, enhanced DNA repair capacity such as HRR or NHEJ leads to resistance to radiotherapy. HRR is a template-driven and thus error-free DNA repair mechanism that involves many proteins
n4:mentions: n2:20832013

Subject Item: _:vb24477709
rdf:type: n4:Context
rdf:value: NHEJ is a more error-prone mechanism that operates with DNA repair proteins such as Ku70/80, XRCC4, XRCC1, DNA-PK, and XLF [>>25<<]. In the current study, we showed that inhibition of both EGFR and IGF1R was able to suppress HRR repair of damaged DNA after γ-irradiation, but not NHEJ repair. This explains why the combination of these two inhibitors could
n4:mentions: n2:20832013

Subject Item: _:vb24477710
rdf:type: n4:Context
rdf:value: This explains why the combination of these two inhibitors could synergistically inhibit HRR, but only showing additive effect on DSB repair inhibition, consistent with previous studies that NHEJ is the main mechanism of DSB repair [>>26<<].
n4:mentions: n2:16822724

Subject Item: _:vb24477711
rdf:type: n4:Context
rdf:value: Both signaling pathways including the downstream signaling cascades are activated in response to ionizing radiation [>>27<<]. Upon their activation, the PI3K-AKT and Ras-MAPK pathways present specific activity toward resistance to chemo- and radio-therapy, in addition to their regulatory capability on cell viability, apoptosis and cell proliferation [28], [29]:
n4:mentions: n2:12600231

Subject Item: _:vb24477712
rdf:type: n4:Context
rdf:value: Upon their activation, the PI3K-AKT and Ras-MAPK pathways present specific activity toward resistance to chemo- and radio-therapy, in addition to their regulatory capability on cell viability, apoptosis and cell proliferation [>>28<<], [29]: The Ras-MAPK pathway stimulates production of EGFR ligand and in turn activates EGFR in an autocrine manner, while PI3K-AKT pathway directly activates the catalytic subunit of DNA-PK, the essential component for NHEJ machinery. The
n4:mentions: n2:16464571

Subject Item: _:vb24477713
rdf:type: n4:Context
rdf:value: Upon their activation, the PI3K-AKT and Ras-MAPK pathways present specific activity toward resistance to chemo- and radio-therapy, in addition to their regulatory capability on cell viability, apoptosis and cell proliferation [28], [>>29<<]: The Ras-MAPK pathway stimulates production of EGFR ligand and in turn activates EGFR in an autocrine manner, while PI3K-AKT pathway directly activates the catalytic subunit of DNA-PK, the essential component for NHEJ machinery.
n4:mentions: n2:16721365

Subject Item: _:vb24477714
rdf:type: n4:Context
rdf:value: However, in IGF1R pathway, Trojanek et al. demonstrated that upon IGF-I stimulation, IRS1, the major IGF1R substrate, binds with Rad51, stimulates nuclear localization of the latter to the site of damaged DNA, and promotes HRR [>>24<<].
n4:mentions: n2:14559999

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