Targeting DYRK1B suppresses the proliferation and migration of liposarcoma cells

Abstract

Liposarcoma is a common subtype of soft tissue sarcoma and accounts for 20% of all sarcomas. Conventional chemotherapeutic agents have limited efficacy in liposarcoma patients. Expression and activation of serine/threonine-protein kinase dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1B (DYRK1B) is associated with growth and survival of many types of cancer cells. However, the role of DYRK1B in liposarcoma remains unknown. In this study, we investigated the functional and therapeutic relevance of DYRK1B in liposarcoma. Tissue microarray and immunohistochemistry analysis showed that higher expression levels of DYRK1B correlated with a worse prognosis. RNA interference-mediated knockdown of DYRK1B or targeting DYRK1B with the kinase inhibitor AZ191 inhibited liposarcoma cell growth, decreased cell motility, and induced apoptosis. Moreover, combined AZ191 with doxorubicin demonstrated an increased anti-cancer effect on liposarcoma cells. These findings suggest that DYRK1B is critical for the growth of liposarcoma cells. Targeting DYRK1B provides a new rationale for treatment of liposarcoma.

The DYRK Family of Kinases in Cancer: Molecular Functions and Therapeutic Opportunities

“…The first studies into the influence of DYRK1B in cancer suggested a role in the survival of cancer cells, with a stronger DYRK1B expression in CRC samples than in normal tissue [ 95 ]. Several studies extended this finding to other tumor types, included liposarcoma [ 96 ], rhabdomyosarcoma [ 97 ], osteosarcoma [ 98 ], lung [ 99 ], breast [ 100 ], ovary [ 101 ] and PDAC [ 68 , 102 , 103 ]. Indeed, a differential expression analysis using TCGA data finds DYRK1B to be overexpressed in several tumor types, including bladder (BLCA); breast (BRCA); kidney (KICH, KIRC and KIRP); liver (LIHC); prostate (PRAD); thyroid (THCA) and uterus (UCEC) ( Table S1 ).…”

“…The latter would enhance the effectiveness of other antiproliferative drugs in combinatorial approaches. For instance, the DYRK1B inhibitor AZ191 [ 52 ] increases the anticancer effects of doxorubicin in liposarcoma cell lines [ 96 ] or sensitizes the PDAC cell lines to mTOR inhibition [ 115 ]. However, AZ191 has been also shown to counteract the antitumor effects of the lysosome inhibitor Bafilomycin A1 in HCC cell lines [ 111 ].…”

Minibrain-related kinase/dual-specificity tyrosine-regulated kinase 1B implication in stem/cancer stem cells biology

“…The human DYRK1B gene is located on chromosome 19q13.2, a region often amplified in ovarian and pancreatic cancer[ 37 - 42 ]. DYRK1B is especially highly expressed in colon carcinoma[ 36 , 43 , 44 ], prostate carcinoma[ 24 , 45 - 47 ], lung cancer[ 45 ], pancreatic ductal adenocarcinomas[ 37 , 48 - 52 ], rhabdo-myosarcomas[ 53 ], osteosarcoma[ 54 ], and liposarcoma[ 55 ]. Also, overexpression of DYRK1B has been reported in breast cancer[ 56 - 58 ], cervical cancer[ 59 , 60 ], and mela-noma[ 61 , 62 ].…”

“…As we have discussed above, DYRKs comprise a family of kinases which are key regulators of signal transduction, cell proliferation, survival, and differentiation[ 18 ]. In particular, DYRK1B is a multifunctional dual-specificity kinase involved in cell cycle progression, differentiation and cell viability[ 42 , 69 , 70 ], and plays key roles in a variety of physiological developmental processes during myogenesis[ 69 , 70 , 74 ], spermatogenesis[ 77 ], neurogenesis[ 35 ] and cell motility[ 55 ], as well as in as in human diseases, such as cancer[ 24 , 36 , 39 , 41 , 50 ] and metabolic syndrome[ 76 ].…”

“…It is possible that motility induced by oncogenic KRAS was due to DYRK1B activity[ 37 ]. In contrast, another study has shown that inhibition of DYRK1B suppresses the proliferation and migration of liposarcoma cells, indicating a positive role for DYRK1B in cell motility[ 55 ]. In particular, DYRK1B targeting in liposarcoma cells, with small molecule inhibitor AZ191 or RNAi-mediated knockdown, results in reduction of proliferation, as well as in suppression of cell motility, induction of apoptosis, and sensitization of liposarcoma cells to chemotherapy drugs, indicating that DYRK1B could play a significant role in liposarcoma cell growth and proliferation motility[ 55 ].…”