Enforced dual‐specificity tyrosine‐regulated kinase 2 expression by adenovirus‐mediated gene transfer inhibits tumor growth and metastasis of colorectal cancer

Abstract

Colorectal cancer is one of the most common gastrointestinal tumors with good outcomes; however, with distant metastasis, the outcomes are poor. Novel treatment methods are urgently needed. Our in vitro studies indicate that dual‐specificity tyrosine‐regulated kinase 2 (DYRK2) functions as a tumor suppressor in colorectal cancer by regulating cell survival, proliferation, and apoptosis induction. In addition, DYRK2 expression is decreased in tumor tissues compared to nontumor tissues in colorectal cancer, indicating a correlation with clinical prognosis. In this context, we devised a novel therapeutic strategy to overexpress DYRK2 in tumors by adenovirus‐mediated gene transfer. The present study shows that overexpression of DYRK2 in colon cancer cell lines by adenovirus inhibits cell proliferation and induces apoptosis in vitro. Furthermore, in mouse subcutaneous xenograft and liver metastasis models, enforced expression of DYRK2 by direct or intravenous injection of adenovirus to the tumor significantly inhibits tumor growth. Taken together, these findings show that adenovirus‐based overexpression of DYRK2 could be a novel gene therapy for liver metastasis of colorectal cancer.

DYRK2 promotes chemosensitivity via p53‐mediated apoptosis after DNA damage in colorectal cancer

“…32 Therefore, DYRK2 may contribute to increased response rates and may be a key marker for these new treatments and potential therapeutic applications in the future. 18 In conclusion, we showed that DYRK2 expression was associated with chemosensitivity to 5-FU and oxaliplatin in p53 wild-type CRC cells. Routine preoperative measurements of the p53 status and DYRK2 expression may be useful for predicting patient sensitivity and in the selection of new therapeutic strategies for patients undergoing chemotherapy for CRC.…”

“…A previous study showed that DYRK2 induced p53‐regulated apoptosis‐inducing protein 1 expression and DNA damage‐triggered apoptosis in a p53‐Ser46 phosphorylation‐dependent manner 14 . Additionally, overexpression of DYRK2 in CRC cell lines using Ad‐DYRK2‐WT induced p53‐Ser46 phosphorylation 18 . Therefore, we initially examined the expression levels of p53‐Ser46 phosphorylation in parental and DYRK2‐KO cells under basal conditions.…”

“…Parental and DYRK2‐KO cells were plated onto six‐well culture plates with 5‐FU or oxaliplatin. After 48 h, the cells were treated according to the manufacturer's instructions (Annexin V‐FITC Apoptosis Detection Kit, Nacalai Tesque) and analyzed using a MACS Quant flow cytometer (Miltenyi Biotec) as previously described 18 . The numbers of apoptotic cells were defined as the total of annexin V+/PI– (early apoptosis) and annexin V+/PI+ (late apoptosis).…”

“…After 48 h, the cells were treated according to the manufacturer's instructions (Annexin V-FITC Apoptosis Detection Kit, Nacalai Tesque) and analyzed using a MACS Quant flow cytometer (Miltenyi Biotec) as previously described. 18 The numbers of apoptotic cells were defined as the total of annexin V+/PI-(early apoptosis) and annexin V+/PI+ (late apoptosis). The quantification of apoptosis was carried out using FlowJo software.…”

“…Dual‐specificity tyrosine‐regulated kinase 2 (DYRK2) is a protein kinase of the DYRK family that primarily localizes in the cytoplasm and shows intracellular serine/threonine kinase activity 13 . DYRK2 functions as a pro‐apoptotic kinase that induces apoptosis in response to DNA damage through p53‐Ser46 phosphorylation in the nucleus 14,15 Previous studies have shown that DYRK2 acts as a tumor suppressor in various cancers triggering major antitumor and pro‐apoptotic signals 16–18 . Clinically, low DYRK2 expression has been associated with poor prognosis in CRC 17,19 .…”