Direct conversion of osteosarcoma to adipocytes by targeting TNIK

Abstract

Osteosarcoma (OS) is an aggressive mesenchymal tumor for which no molecularly targeted therapies are available. We have previously identified TRAF2- and NCK-interacting protein kinase (TNIK) as an essential factor for the transactivation of Wnt signal target genes and shown that its inhibition leads to eradication of colorectal cancer stem cells. The involvement of Wnt signaling in the pathogenesis of OS has been implicated. The aim of the present study was to examine the potential of TNIK as a therapeutic target in OS. RNA interference or pharmacological inhibition of TNIK suppressed the proliferation of OS cells. Transcriptome analysis suggested that a small-molecule inhibitor of TNIK upregulated the expression of genes involved in OS cell metabolism and downregulated transcription factors essential for maintaining the stem cell phenotype. Metabolome analysis revealed that this TNIK inhibitor redirected the metabolic network from carbon flux toward lipid accumulation in OS cells. Using in vitro and in vivo OS models, we confirmed that TNIK inhibition abrogated the OS stem cell phenotype, simultaneously driving conversion of OS cells to adipocyte-like cells through induction of PPARγ. In relation to potential therapeutic targeting in clinical practice, TNIK was confirmed to be in an active state in OS cell lines and clinical specimens. From these findings, we conclude that TNIK is applicable as a potential target for treatment of OS, affecting cell fate determination.

Validation of Gene Expression-Based Predictive Biomarkers for Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer

“…It has been reported that GPR110 ( ADGRF1 ) can induce cell cycle arrest and chemoresistance in breast cancer [ 32 ]. TNIK appeared to be an essential factor for WNT signaling and stemness in colorectal cancer [ 33 ] and might be responsible for chemoresistance in osteosarcoma [ 34 ]. However, the 4-gene signature, consisting of GPR110 , TNIK , WDR4, and BRCA1 , showed no association with nCRT response in any of the validation cohorts of LARC biopsies.…”

BAIAP2L2 promotes the proliferation, migration and invasion of osteosarcoma associated with the Wnt/β-catenin pathway

“…Extensive studies have shown that modulation of some specific RNAs could result in activation or inactivation of the Wnt/β-catenin signaling pathway in human cancers, including gastrointestinal cancers [21] , prostate cancer [22] , breast cancer [11] and many others [23] , [24] . Recently, two reports have also revealed the activated status of Wnt/β-catenin signaling pathway in Osteosarcoma [25] , [26] . Our results from transwell assay, migration assay, and invasion assay confirmed that down-regulation of BAIAP2L2 inhibited cell migration/invasion and induced the inactivation of Wnt /β-catenin pathway.…”

Biological evidence of cancer stem-like cells and recurrent disease in osteosarcoma

“…Repressing the signaling pathways related to the maintenance of CSCs (see Table 1) resulted in the slowdown of tumor growth and inhibition of the metastatic process [105][106][107][108][109][110][111][112][113][114][115][116] . As previously mentioned, Wnt/βcatenin appeared crucial for the maintenance of CSCs and its attenuation by using tankyrase inhibitor, or tegavivint was associated with a decrease in both CSC numbers and tumor progression [105,106] .…”

“…Drugs targeting transcription factors (e.g., STAT-3 and STAT5) controlling the development of CSCs may also be used to improve the therapeutic approaches to osteosarcoma [75,111,112] . Activation of hormone signaling can reduce stemness in osteosarcoma, as shown by the activation of estrogen receptor alpha by decitabine [113] . Most cytokineinduced signaling pathways result in the translocation of transcription factors which modulate the transcription of target genes.…”

“…Similarly, ROCK inhibition by fasudil suppressed in vitro cell BMP2 BMP2 receptor signaling [110] Other receptor signaling targeting (STAT-3, STAT-5, ER-α, TRAF-2, etc.) and transcription factors Bruceine D STAT-3 inhibition [111] Pimozide STAT-5 signaling [75,112] Decitabine Activation of estrogen receptor alpha (ER-α) [113] NCB-0846 TRAF2-and NCK-interacting protein kinase [114] Melatonin Suppression of SOX9 mediated signaling [115] Statins KLF4 [116] Targeting of kinase activities Fasudil Rho-associated coiled-coil containing kinase (ROCK) inhibition [100] Autophagy and metabolic targeting Thioridazine Autophagy [94] -Inhibition of mitochondrial functions (decrease in oxygen assumption, decreased mitochondrial membrane potential, decreased ATP production) [117] -Pyruvate kinase isoenzyme M2 (PKM2) [118] -ROS-mediated apoptosis and autophagy [119] Metfomin -Activation and phosphorylation of the energetic sensor AMPK [120] Wogonin ROS regulation [121] DMAMCL Cell cycle [122] DAPT γ-secretase inhibition [123] Combinations with chemotherapy and sensitization to chemotherapy Ascorbate Sensitization to cisplatin [124] Ouabain Sensitization to cisplatin: Na + /K + ATPase inhibition [125] Tangeretin -Disruption of the DNMT1/miR34a/Bcl-2 axis by isovitexin [85] -lncRNA HOXD-AS1 knockdown [92] -RAB39A silencing [99] Epigenetic targeting -Targeting of lncRNA SOX2OT variant 7 by EGCG (polyphenol isolated from green tea) [130] Photo therapy -Graphene oxide nanoparticle-loaded ginsenoside Rg3…”