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TG‐interacting Factor Can Elicit Hedgehog Pathway to Increase Resistance to Gemcitabine in Urothelial Carcinoma
Author(s) -
Huang HueiSheng,
Huang YueJhu
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.934.5
Subject(s) - gemcitabine , hedgehog signaling pathway , smoothened , hedgehog , cancer research , protein kinase b , gli1 , medicine , chemistry , signal transduction , biology , cancer , microbiology and biotechnology
Urothelial carcinoma (UC) of the bladder is the 4 th most commonly diagnosed cancer and the 8 th most common cancer‐related death in male in the United States in 2016. Using gemcitabine/cisplatin as a chemotherapy after surgery of patients with UC is a common treatment. However, the drug‐resistance to the therapy and high recurrence of UC patients usually occurred. Previously, we have demonstrated that TG‐interacting factor (TGIF) is involved in the migration/invasion, poor prognosis, and gemcitabine‐resistance of UC via PI3K/AKT pathway. It also has been proven that the aberrant hedgehog pathway is associated with many cancers and drug‐resistance. Therefore, whether the hedgehog pathway was involved in the gemcitabine‐resistance of UC was addressed. In the present study, we observed that expression of TGIF, pAKT ser473 , pGSK3β ser9 and hedgehog components (Gli2, Smo, and Ptch) was increased in gemcitabine‐resistant NTUB1 (NGR) cells. Overexpression of TGIF or AKT1 in NTUB1 cells increased activity of GLI‐luciferase reporter and Gli2 expression. Furthermore, overexpression of AKT1 could phosphorylate pGSK3β ser9 to inactivate its kinase activity and induce activation of hedgehog pathway. In addition, overexpression of GSKS9D could inactivate GSK3β kinase and increase activity of hedgehog pathway. However, overexpression of GSKS9A could activate GSK3β kinase to suppress hedgehog pathway activation. Finally, overexpression of Gli2 increased resistance to gemcitabine in NTUB1 cells, whereas, knockdown of Gli2 reduced resistance to gemcitabine in NGR cells. Accordingly, we suggest that gemcitabine‐induced TGIF expression can activate AKT/GSK3β signaling to elicit hedgehog pathway, which results in the gemcitabine resistance of UC. Support or Funding Information This work was supported by grants from the National Science Council (Taipei, Taiwan; NSC102‐2321‐B‐006‐019‐MY2; MOST104‐2314‐B‐006‐055‐MY3)