Rab5C enhances resistance to ionizing radiation in rectal cancer

Baptistella, Antuani Rafael; Landemberger, Michele Christine; Dias, Maria Assunção Faus da Silva; Giudice, Fernanda Salgueiredo; Rodrigues, Bruna R.; Silva, Petrus Paulo Combás Eufrazio Da; Cassinela, Edson Kuatelela; Lacerda, Tonielli Cristina Sousa de; Marchi, Fábio Albuquerque; Leme, Adriana Franco Paes; Begnami, María Dirlei; Aguiar, Samuel; Martins, Vilma R.

doi:10.1007/s00109-019-01760-6

Cited by 20 publications

(15 citation statements)

References 46 publications

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“…Specifically, in CRC cells, WNT activity was previously associated with ionizing radiation resistance [34,35]. More recently, internalization of epidermal growth factor receptor (EGFR) by Rab5C was suggested to enhance resistance to ionizing radiation in rectal cancer [36]. In a different context, tetraploid cells induced by cell fusion hybrids display great capacity to nuclear reprogramming as a consequence of activating the WNT/β-catenin signaling pathway [37].…”

Section: Discussionmentioning

confidence: 99%

Tetraploidy-Associated Genetic Heterogeneity Confers Chemo-Radiotherapy Resistance to Colorectal Cancer Cells

Galofré

Geyik

Asensio

et al. 2020

Cancers

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Tetraploidy, or whole-genome duplication, is a common phenomenon in cancer and preludes chromosome instability, which strongly correlates with disease progression, metastasis, and treatment failure. Therefore, it is reasonable to hypothesize that tetraploidization confers multidrug resistance. Nevertheless, the contribution of whole-genome duplication to chemo-radiotherapy resistance remains unclear. Here, using isogenic diploid and near-tetraploid clones from three colorectal cancer cell lines and one non-transformed human epithelial cell line, we show a consistent growth impairment but a divergent tumorigenic potential of near-tetraploid cells. Next, we assessed the effects of first-line chemotherapeutic drugs, other commonly used agents and ionizing radiation, and found that whole-genome duplication promoted increased chemotherapy resistance and also conferred protection against irradiation. When testing the activation of apoptosis, we observed that tetraploid cells were less prone to caspase 3 activation after treatment with first-line chemotherapeutic agents. Furthermore, we found that pre-treatment with ataxia telangiectasia and Rad3 related (ATR) inhibitors, which targets response to replication stress, significantly enhanced the sensitivity of tetraploid cells to first-line chemotherapeutic agents as well as to ionizing radiation. Our findings provide further insight into how tetraploidy results in greater levels of tolerance to chemo-radiotherapeutic agents and, moreover, we show that ATR inhibitors can sensitize near-tetraploid cells to commonly used chemo-radiotherapy regimens.

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Section: Discussionmentioning

confidence: 99%

Tetraploidy-Associated Genetic Heterogeneity Confers Chemo-Radiotherapy Resistance to Colorectal Cancer Cells

Galofré

Geyik

Asensio

et al. 2020

Cancers

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“…Radiation-induced cell death initiates from the mass generation of ROS, which subsequently causes DNA doublestrand break and, consequently, apoptosis or necrosis (33). Previous studies have already identified multiple different possibilities to speculate the causes of the development of radioresistance in rectal cancer, including DNA repair system (34)(35)(36)(37)(38)(39), apoptosis and cell survival (36,(38)(39)(40)(41), epithelialmesenchymal transition (EMT) (37,42), tumor stem cell (43), and the generation of ROS (44), suggesting that the process of radioresistance-development may be complex.…”

Section: Discussionmentioning

confidence: 99%

“…For DNA repair system-related mechanisms, Ha Thi et al reported that miR-130a targets sex determining region Y-box 4 (SOX4) and thus activates downstream ataxia-telangiectasia mutated (ATM)-mediated DNA repair (37). Rab5 and replication factor C subunit 4 (RFC4) are demonstrated to facilitate the expression of non-homologous end joining DNA repair-related proteins, Ku70 and Ku80 (34,35). In another recent study by Ferrandon et al, knocking down coenzyme A synthase (COASY) hindered DNA double-strand break (38).…”

Section: Discussionmentioning

confidence: 99%

PITPNC1 fuels radioresistance of rectal cancer by inhibiting reactive oxygen species production

Tan

Shao

et al. 2020

Ann Transl Med

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Background: Neoadjuvant radiotherapy is a commonly used method for the current standard-of-care for most patients with rectal cancer, when the effects of radioresistance are limited. The phosphatidylinositol transfer protein, cytoplasmic 1 (PITPNC1), a lipid-metabolism-related gene, has previously been proved to manifest pro-cancer effects in multiple types of cancer. However, whether PITPNC1 plays a role for developing radioresistance in rectal cancer patients is still unknown. Therefore, this study aims to investigate the role of PITPNC1 in rectal cancer radioresistance.Methods: Patient-derived tissue were used to detect the difference in the expression level of PITPNC1 between radioresistant and radiosensitive patients. Bioinformatic analyses of high-throughput gene expression data were applied to uncover the correlations between PITPNC1 level and oxidative stress. Two rectal cancer cell lines, SW620, and HCT116, were selected in vitro to investigate the effect of PITPNC1 on radioresistance, reactive oxygen species (ROS) generation, apoptosis, and proliferation in rectal cancer.Results: PITPNC1 is highly expressed in radioresistant patient-derived rectal cancer tissues compared to radiosensitive tissue; therefore, PITPNC1 inhibits the generation of ROS and improves the extent of radioresistance of rectal cancer cell lines and then inhibits apoptosis. Knocking down PITPNC1 facilitates the production of ROS while application of the ROS scavenger, N-acetyl-L-cysteine (NAC), could reverse this effect.Conclusions: PITPNC1 fuels radioresistance of rectal cancer via the inhibition of ROS generation.

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“…Interestingly, EGFR pathway activation stimulates DSB repair, and this was traced, at least in part, to an interaction between AKT1 and DNA-PKcs [187] . In a parallel EGFR pathway, radioresistance of tumor cells that overexpress Rab5C, Ku70, and Ku80 was traced to Rab5C regulation of EGFR internalization and its translocation to the nucleus, where EGFR stimulates Ku70/Ku80 expression [188] . Cetuximab, a clinically useful monoclonal antibody that targets EGFR, inhibits DNA-PKcs [158] and enhanced radiotherapy in early clinical trials to treat cutaneous squamous cell carcinoma [159] .…”

Section: Targeting Nhejmentioning

confidence: 99%

Exploiting DNA repair pathways for tumor sensitization, mitigation of resistance, and normal tissue protection in radiotherapy

Nickoloff¹,

Taylor²,

Sharma³

et al. 2021

CDR

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More than half of cancer patients are treated with radiotherapy, which kills tumor cells by directly and indirectly inducing DNA damage, including cytotoxic DNA double-strand breaks (DSBs). Tumor cells respond to these threats by activating a complex signaling network termed the DNA damage response (DDR). The DDR arrests the cell cycle, upregulates DNA repair, and triggers apoptosis when damage is excessive. The DDR signaling and DNA repair pathways are fertile terrain for therapeutic intervention. This review highlights strategies to improve therapeutic gain by targeting DDR and DNA repair pathways to radiosensitize tumor cells, overcome intrinsic and acquired tumor radioresistance, and protect normal tissue. Many biological and environmental factors determine tumor and normal cell responses to ionizing radiation and genotoxic chemotherapeutics. These include cell type and cell cycle phase distribution; tissue/tumor microenvironment and oxygen levels; DNA damage load and quality; DNA repair capacity; and susceptibility to apoptosis or other active or passive cell death pathways. We provide an overview of radiobiological parameters associated with X-ray, proton, and carbon ion radiotherapy; DNA repair and DNA damage signaling pathways; and other factors that regulate tumor and normal cell responses to radiation. We then focus on recent studies exploiting DSB repair pathways to enhance radiotherapy therapeutic gain.

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Rab5C enhances resistance to ionizing radiation in rectal cancer

Cited by 20 publications

References 46 publications

Tetraploidy-Associated Genetic Heterogeneity Confers Chemo-Radiotherapy Resistance to Colorectal Cancer Cells

Tetraploidy-Associated Genetic Heterogeneity Confers Chemo-Radiotherapy Resistance to Colorectal Cancer Cells

PITPNC1 fuels radioresistance of rectal cancer by inhibiting reactive oxygen species production

Exploiting DNA repair pathways for tumor sensitization, mitigation of resistance, and normal tissue protection in radiotherapy

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