Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Medullary thyroid carcinoma (MTC) originates from the C cells of the thyroid gland, which secrete calcitonin. Lymph node and distant metastases are frequently present at diagnosis. Activating mutations of RET, a driver oncogene in MTC that encodes a tyrosine kinase receptor, prevents apoptosis through inhibition of ATF4, a key transcriptional regulator of endoplasmic reticulum (ER) stress. We hypothesized that the combination of a tyrosine kinase inhibitor (TKI) and an ATF4 inducer promotes cell death by triggering catastrophic oxidative stress and apoptotic cell death. Here, we report that the ER-associated protein degradation (ERAD) inhibitor eeyarestatin sensitized MTC cells to the TKIs, sunitinib and vandetanib, thereby leading to synergistic upregulation of ATF4 expression, accumulation of reactive oxygen species, and subsequent cell death. Genome-wide analysis of ATF4 interaction sites by chromatin immunoprecipitation (ChIP) sequencing revealed that among ATF4 target genes was KLF9 (Kruppel-like factor 9), which induces MTC apoptosis. ChIP assays revealed that ATF4 occupancy at the KLF9 promoter was increased in MTC cells treated with eeyarestatin or vandetanib alone and was further enhanced in cells treated with both drugs, leading to increased KLF9 transcription. Depletion of ATF4 by shRNA led to downregulation of KLF9 expression and prevented oxidative stress-induced cell death. Furthermore, we identified ATF4 target genes (LZTFL1, MKNK2, and SIAH1 with known tumor suppressor function) that were synergistically upregulated with the combination of TKI and ERAD inhibitor. IMPLICATIONS: These findings reveal a combination therapy that induces reactive oxygen species-dependent catastrophic cell death through induction of ATF4 and KLF9 transcriptional activity.
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PMID:Combinations of Tyrosine Kinase Inhibitor and ERAD Inhibitor Promote Oxidative Stress-Induced Apoptosis through ATF4 and KLF9 in Medullary Thyroid Cancer. 3055 30

Sphingosine kinases 1 and 2 (SK1 and SK2) are proto-oncogenic isozymes expressed in many human tumors and associated with chemoresistance and poor prognosis. They are well-recognized therapy targets and their inhibition was shown to induce tumor volume reduction and chemosensitization in multiple cancer models. Oncogenic signaling is extremely complex and often cross-regulated. Designing molecular therapies and their combinations requires rational approaches to avoid redundant targeting or developing resistance. In this study, we have performed RNA transcriptome microarray analysis of two breast and two prostate metastatic cancer cell lines treated with siRNAs targeting SK1 or SK2. In prostate cancer cell lines SK1 knockdown (KD) has significantly changed expression of several genes including downregulation of NSUN2, G3BP2 and upregulation of ETS1. SK2 KD also affected expression of multiple genes including downregulation of CAPZA1 NSUN3 and ADPGK and upregulation of VDAC1, IBTK, ETS1, and MKNK2. Similarly, in breast cancer cells SK1 KD led to downregulation of NSUN2, NFATC3, CDK2, and G3BP2 and upregulation of GTF2B, TTC17, and RAB23. SK2 KD in breast cancer cells has decreased expression of ITGAV and CAPZA1 and increased expression of GTF2B and ST13. Gene-set enrichment analysis of known biochemical pathways showed that in prostate and breast cell lines SKs KD have altered multiple pathways. SK1 KD altered chromatin assembly, regulation of G1/S transition and mitosis, Wnt and MAP kinase signaling and cell motility. SK2 KD altered RAS protein signal transduction, regulation of MAP kinase and serine/threonine kinase activity, cell motility, small GTPase mediated signal transduction and phosphatidylinositol 3-kinase (PI3K) signaling. Through genome-wide microarray analysis, we have identified important molecular pathways affected by SK1 and SK2 KD. It appears that while KD of both genes leads to a decrease in individual pro-tumorigenic genes, there is a universal cellular response resulting in upregulation of several known pro-survival and pro-tumorigenic pathways such as MAPK, RAS, and PI3K, which may mediate cancer resistance to anti-SKs therapies. Our data point out to the potential advantage of certain molecular therapy combinations in targeting prostate and breast cancer. Further signaling studies are required to confirm the individual involvement of identified pathways.
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PMID:Transcriptome-Wide Effects of Sphingosine Kinases Knockdown in Metastatic Prostate and Breast Cancer Cells: Implications for Therapeutic Targeting. 3097 29