DYRK1A suppression attenuates HIF‑1α accumulation and enhances the anti‑liver cancer effects of regorafenib and sorafenib under hypoxic conditions

Abstract

Hypoxia promotes drug resistance and induces the expression of hypoxia inducible factor (HIF)-1α in liver cancer cells. However, to date, no selective HIF-1α inhibitor has been clinically approved. The aim of this study is to investigate a drug-targetable molecule that can regulate HIF-1α under hypoxia. The present study demonstrated that hyperactivation of dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A)/HIF-1α signaling was associated with an increased risk of liver cancer. In addition, DYRK1A knockdown using small interfering RNA transfection or treatment with harmine, a natural alkaloid, significantly reduced the protein expression levels of HIF-1α in liver cancer cells under hypoxic conditions in vitro. Conversely, DYRK1A overexpression-vector transfection in liver cancer cell lines notably induced HIF-1α expression under the same conditions. Furthermore, DYRK1A was shown to interact and activate STAT3 under hypoxia to regulate HIF-1α expression. These findings indicated that DYRK1A may be a potential upstream activator of HIF-1α and positively regulate HIF-1α via the STAT3 signaling pathway in liver cancer cells. Additionally, treatment with harmine attenuated the proliferative ability of liver cancer cells under hypoxic conditions using sulforhodamine B and colony formation assay. Furthermore, DYRK1A knockdown could significantly enhance the anti-liver cancer effects of regorafenib and sorafenib under hypoxia. Co-treatment with harmine and either regorafenib or sorafenib also promoted cell death via the STAT3/HIF-1α/AKT signaling pathway under hypoxia using PI staining and western blotting. Overall, the results from the present study suggested that DYRK1A/HIF-1α signaling may be considered a novel pathway involved in chemoresistance, thus providing a potentially effective therapeutic regimen for treating liver cancer.

MicroRNA-221-3p inhibits the inflammatory response of keratinocytes by regulating the DYRK1A/STAT3 signaling pathway to promote wound healing in diabetes

“…STAT3 is a substrate of DYRK1A 19 . Therefore, we used Co-IP assays to confirm that DYRK1A also interacts with the STAT3 protein in HaCaT cells, which is consistent with previous reports 21 . Our results also showed that HG significantly increased DYRK1A expression and enhanced STAT3 phosphorylation at Try705 and Ser727.…”

“…Previous studies have reported that signal transducer and activator of transcription 3 (STAT3) is a substrate of DYRK1A 19 , 21 . Thus, to identify the molecular mechanism underlying the effects of DYRK1A, we used co-immunoprecipitation (Co-IP) assays with HaCaT cell lysates to find that DYRK1A and STAT3 reciprocally pulled down each other (Fig.…”

POLR2J is a potential biomarker for abnormal tumor progression, vorinostat sensitization, immune infiltration, and prognosis of glioblastoma multiform

“…After 24 h siRNA transfection, U251 and A172 cells were cultured into 96-well plates at a density of 3 × 10 3 cells/well. At 30-50% con uence, cells were treated with 1-6 µM vorinostat at 37°C for 72 h. The following steps are performed as described previously [14]. The OD value was detected at 540 nm with a microplate reader (Bioteck, Winooski, VT, USA).…”

HIF‐1α regulates the cell viability in radioiodine‐resistant papillary thyroid carcinoma cells induced by hypoxia through PKM2/NF‐κB signaling pathway

“…10 The increased expression of HIF-1α mediates the tumor cell invasion, aging, cancer stem cell-like phenotype, and resistance to chemotherapy or radioiodine. 11,12 RAI is safe and effective modality used to prevent PTC and generally used in radiotherapy. 13 However, the resistance to radioiodine therapy has become the major challenge.…”

“…In the process of hypoxic, hypoxia‐inducible factor 1α (HIF‐1α) is a potential regulator of the cellular response to the low oxygen environment 10 . The increased expression of HIF‐1α mediates the tumor cell invasion, aging, cancer stem cell‐like phenotype, and resistance to chemotherapy or radioiodine 11,12 …”