SiRNA-mediated IGF-1R inhibition sensitizes human colon cancer SW480 cells to radiation

Yavari, Kamal; Taghikhani, Mohammad; Maragheh, Mohammad Ghannadi; Mesbah-Namin, Seyed A.; Babaei, Mohammad Hosein; Arfaee, Ali Jabbary; Hossein, Moulavi

doi:10.3109/02841860903334429

Cited by 19 publications

(7 citation statements)

References 35 publications

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“…This dual radioprotective effect of IGF1R signaling in GSCs has critical implications in the outcome of fractionated radiation. Inhibition of IGF1R has been found to sensitize human brain, breast, prostate, colon cancer, osteosarcoma, and lung cancer cell lines to radiation [55–59]. We have now further shown that it also attenuates acquired radioresistance in GSCs, which suggests that IGF1R blockade is an important strategy in the prevention of recurrence after radiotherapy.…”

Section: Discussionmentioning

confidence: 66%

IGF1 Receptor Signaling Regulates Adaptive Radioprotection in Glioma Stem Cells

et al. 2013

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Cancer stem cells (CSCs) play an important role in disease recurrence after radiation treatment as a result of intrinsic properties such as high DNA repair capability and antioxidative capacity. It is unclear, however, how CSCs further adapt to escape the toxicity of the repeated irradiation regimens used in clinical practice. Here, we have exposed a population of murine glioma stem cells (GSCs) to fractionated radiation in order to investigate the associated adaptive changes, with the ultimate goal of identifying a targetable factor that regulates acquired radioresistance. We have shown that fractionated radiation induces an increase in IGF1 secretion and a gradual upregulation of the IGF type 1 receptor (IGF1R) in GSCs. Interestingly, IGF1R upregulation exerts a dual radioprotective effect. In the resting state, continuous IGF1 stimulation ultimately induces downregulation of Akt/ extracellular-signal-regulated kinases (ERK) and FoxO3a activation, which results in slower proliferation and enhanced self-renewal. In contrast, after acute radiation, the abundance of IGF1R and increased secretion of IGF1 promote a rapid shift from a latent state toward activation of Akt survival signaling, protecting GSCs from radiation toxicity. Treatment of tumors formed by the radioresistant GSCs with an IGF1R inhibitor resulted in a marked increase in radiosensitivity, suggesting that blockade of IGF1R signaling is an effective strategy to reverse radioresistance. Together, our results show that GSCs evade the damage of repeated radiation not only through innate properties but also through gradual inducement of resistance pathways and identify the dynamic regulation of GSCs by IGF1R signaling as a novel mechanism of adaptive radioprotection.

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Section: Discussionmentioning

confidence: 66%

IGF1 Receptor Signaling Regulates Adaptive Radioprotection in Glioma Stem Cells

et al. 2013

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“…Very few studies have been conducted on the role of IGF‐1R in resistance to radiation therapy. In multiple studies, it has been shown that suppression of IGF‐1R ROS‐mediated overactivation leads to the decreased radioresistance of different cancers both in vitro and in vivo (Denduluri et al, ; Moreno‐Acosta et al, ; Panganiban & Day, ; Venkatachalam et al, ; Yavari et al, ). In this regard, findings from Afshar () study have shown that inhibition of IGF‐1R by ectopic increase of miR‐185 suppressed radiation‐induced IGF‐1R phosphorylation/overactivation and introduced apoptosis and then radiosensitivity in CRC cell line.…”

Section: Discussionmentioning

confidence: 99%

Let‐7e enhances the radiosensitivity of colorectal cancer cells by directly targeting insulin‐like growth factor 1 receptor

Samadi

Afshar

Amini

et al. 2018

Journal Cellular Physiology

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Abnormal expression of various microRNAs (miRNAs), as regulators of biological signaling pathways, has a strong association with cancer resistance to chemotherapy and radiotherapy. The let‐7 family of miRNAs as tumor suppressors have shown to be downregulated in different types of human malignancies including colorectal cancer (CRC). However, the biological function of let‐7 members in the processes of resistance to radiation in CRC has not yet been completely elucidated. Insulin‐like growth factor 1 receptor (IGF‐1R) signaling pathway is amplified in CRC and leads to its progression, development, and also radiation resistance. So, it seems like an attractive target for anticancer therapy. In this study, by using bioinformatics analysis, it has been revealed that IGF‐1R is a direct target of the let‐7e member. Consistent with this, we identified that increased levels of let‐7e in CRC cells reduced IGF‐1R protein level and subsequently its downstream signaling pathways, which resulted in the G1 cell cycle arrest and a significant reduction in the proliferation, survival and also resistance to radiation of CRC cells. Altogether, these results suggested that let‐7e by targeting the IGF‐1R signaling pathway might serve as therapeutics in anticancer therapy.

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“…Knockdown of IGF1R enhances chemosensitivity to cisplatin in human lung adenocarcinoma A549 cells [30]. Inhibition of IGF1R signaling using RNAi enhances sensitivity to adriamycin chemotherapy liver cancer cell lines [31,32] and the effect of the 5-fluorouracil (5-FU) in SW480 colon cancer cells [33]. In pancreatic cancer xenografts, the chemosensitivity to gemcitabine was enhanced by concomitant treatment with an anti-IGF1R antibody [34].…”

Section: Discussionmentioning

confidence: 99%

Downregulation of IGF1R Expression Inhibits Growth and Enhances Cisplatin Sensitivity of Head and Neck Squamous Cell Carcinoma Cells In Vitro

Khalil

Jameson

2018

HORM CANC

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A lentivirus-mediated doxycycline-inducible pTRIPZ shRNAmir plasmid targeting IGF1R transcript was transfected into two head and neck squamous cell carcinoma (HNSCC) cell lines to silence IGF1R expression and to assess the effect of its downregulation on cisplatin sensitivity in vitro. In Cal27-regIGF1R and SCC25-regIGF1R cell lines, IGF1R protein expression was reduced by more than 90% after 72 h of incubation with doxycycline. Both basal and IGF-stimulated pIGF1R, pAKT, and pERK were significantly reduced, without influence on total AKT and ERK expression. Downregulation of the IGF1R was associated with decreased proliferation and cell viability in both cell lines. Reduced IGF1R expression was also associated with increased sub-G0/G1-phase and G0/G1-phase populations and decreased S-phase and G2/M-phase populations. IGF1R downregulation enhanced sensitivity to cisplatin with decrease of cisplatin IC 50 from 15 to 7.1 in Cal27-regIGF1R cells and from 11 to 6.3 in SCC25-regIGF1R cells. Cisplatin exhibited increased pro-apoptotic activity by annexin V staining and PARP cleavage in both cells lines when cultured in doxycycline. Thus, in two HNSCC cell lines in vitro, reduced IGF1R expression results in reduced growth rate and increased sensitivity to cisplatin. Thus, IGF1R downregulation and/or inhibition may serve as a useful adjunct to platinum-based cytotoxic chemotherapy.

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SiRNA-mediated IGF-1R inhibition sensitizes human colon cancer SW480 cells to radiation

Cited by 19 publications

References 35 publications

IGF1 Receptor Signaling Regulates Adaptive Radioprotection in Glioma Stem Cells

IGF1 Receptor Signaling Regulates Adaptive Radioprotection in Glioma Stem Cells

Let‐7e enhances the radiosensitivity of colorectal cancer cells by directly targeting insulin‐like growth factor 1 receptor

Downregulation of IGF1R Expression Inhibits Growth and Enhances Cisplatin Sensitivity of Head and Neck Squamous Cell Carcinoma Cells In Vitro

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