Abstract
Although chemo- or radiotherapy is usually performed in patients with colorectal cancer, the response is highly variable in locally rectal cancer. Therefore, additional studies are needed on predictable markers and the molecular mechanisms of chemo- and radiotherapy. Y box binding protein 1 (YB1) is an oncoprotein that is aberrantly expressed in many cancers, including colorectal cancer. However, to date there are no targeting agents or strategies to inhibit YB1 expression. Here, we investigate the oncogenic function of YB1 in colorectal cancer and methods to control its expression. We observed that YB1 expression level is correlated with colorectal cancer survival rate. Moreover, YB1 overexpression was associated with colorectal cancer lymph node metastasis and invasion. We also found that radiation exposure increased YB1 expression, which led to radioresistant colorectal cancer, mediated through the activation of cancer stem cell marker CD44 and PI3K/AKT/mTOR signaling. This study revealed, by both in vitro and in vivo assays, that depletion of YB1 could reduce cell proliferation and motility in colorectal cancer. We further demonstrated that the PI3K/mTOR inhibitor BEZ235 suppressed YB1 expression and enhanced the cytotoxicity of radiation. In addition, combined treatment with BEZ235 and radiation showed a significant antitumor response in an in vivo mouse xenograft model. Taken together, our results provide evidence that the activation of YB1 is a major factor in radioresistance and suggest that targeting YB1-mediated signaling is a promising therapeutic strategy for colorectal cancer.
Highlights
Colorectal cancer is one of the most common malignancies worldwide [1]
IR accelerated Y box binding protein 1 (YB1) activation in colorectal cancer cells We first evaluated phosphorylated YB1 (p-YB1) and total basal YB1 levels in various colorectal cancer cell lines. We found that both p-YB1 and total basal YB1 levels were increased in four of the colorectal cancer cell lines, including DLD1, T84, SW837, and SW1463 compared with the other colorectal cancer cell lines (Fig. 2A)
Nuclear YB1 was detected in RKO, SW620, DLD1, and SW837 colorectal cancer cell lines, and these levels were elevated in DLD1 and SW837 cells when compared with RKO and SW620 cells (Fig. 2B)
Summary
Colorectal cancer is one of the most common malignancies worldwide [1]. Surgery is the standard therapy for patients with colorectal cancer, and 20% of the patients show relapse [2]. Preoperative chemo- and radiotherapy are used commonly for colorectal cancer treatment to reduce recurrence [3]. A deeper understanding of the molecular mechanics of radiotherapy resistance is needed for the development of potential therapeutic strategies to improve the survival of patients with colorectal cancer. YB1 is primarily localized in the cytoplasm, but various stimuli, such as DNA-damaging agents or irradiation (IR), can enhance the transcription factor activity of YB1 in the nucleus [7]. For the nuclear accumulation and induction of transcriptional activity, YB1 must be phosphorylated at Ser102 [8]. Phosphorylated and nuclear YB1 levels are a predictive factor for cellular response to DNA damage stressors, Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/)
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