Inhibition of gsk-3 induces differentiation and impaired glucose metabolism in renal cancer

Krishnendu Pal, Ying Cao, Irina N. Gaisina, Santanu Bhattacharya, Shamit K. Dutta, Enfeng Wang, Hendra Gunosewoyo, Alan P. Kozikowski, Daniel D Billadeau, Debabrata Mukhopadhyay

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Glycogen synthase kinase-3 (GSK-3), a constitutively active serine/threonine kinase, is a key regulator of numerous cellular processes ranging from glycogen metabolism to cell-cycle regulation and proliferation. Consistent with its involvement in many pathways, it has also been implicated in the pathogenesis of various human diseases, including type II diabetes, Alzheimer disease, bipolar disorder, inflammation, and cancer. Consequently, it is recognized as an attractive target for the development ofnewdrugs. In the present study,we investigated the effect of both pharmacologic and genetic inhibition of GSK-3 in two different renal cancer cell lines. We have shown potent antiproliferative activity of 9-ING-41, a maleimide-based GSK-3 inhibitor. The antiproliferative activity is most likely caused by G0-G1 and G2-M phase arrest as evident from cell-cycle analysis. We have established that inhibition of GSK-3 imparted a differentiated phenotype in renal cancer cells. We have also shown that GSK-3 inhibition induced autophagy, likely as a result of imbalanced energy homeostasis caused by impaired glucose metabolism. In addition, we have demonstrated the antitumor activity of 9-ING-41 in two different subcutaneous xenograft renal cell carcinoma tumor models. To our knowledge, this is the first report describing autophagy induction due to GSK-3 inhibition in renal cancer cells. Mol Cancer Ther; 13(2); 285-96.

Original languageEnglish (US)
Pages (from-to)285-296
Number of pages12
JournalMolecular Cancer Therapeutics
Volume13
Issue number2
DOIs
StatePublished - Feb 2014

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Glycogen Synthase Kinase 3
Kidney Neoplasms
Glucose
Renal Cell Carcinoma
Autophagy
Cell Cycle
Neoplasms
G2 Phase
Protein-Serine-Threonine Kinases
Glycogen
Bipolar Disorder
Heterografts
Cell Division
Type 2 Diabetes Mellitus
Inhibition (Psychology)
Alzheimer Disease
Homeostasis
Cell Proliferation
Inflammation
Phenotype

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Inhibition of gsk-3 induces differentiation and impaired glucose metabolism in renal cancer. / Pal, Krishnendu; Cao, Ying; Gaisina, Irina N.; Bhattacharya, Santanu; Dutta, Shamit K.; Wang, Enfeng; Gunosewoyo, Hendra; Kozikowski, Alan P.; Billadeau, Daniel D; Mukhopadhyay, Debabrata.

In: Molecular Cancer Therapeutics, Vol. 13, No. 2, 02.2014, p. 285-296.

Research output: Contribution to journalArticle

Pal, Krishnendu ; Cao, Ying ; Gaisina, Irina N. ; Bhattacharya, Santanu ; Dutta, Shamit K. ; Wang, Enfeng ; Gunosewoyo, Hendra ; Kozikowski, Alan P. ; Billadeau, Daniel D ; Mukhopadhyay, Debabrata. / Inhibition of gsk-3 induces differentiation and impaired glucose metabolism in renal cancer. In: Molecular Cancer Therapeutics. 2014 ; Vol. 13, No. 2. pp. 285-296.
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