TY - JOUR
T1 - Inhibition of gsk-3 induces differentiation and impaired glucose metabolism in renal cancer
AU - Pal, Krishnendu
AU - Cao, Ying
AU - Gaisina, Irina N.
AU - Bhattacharya, Santanu
AU - Dutta, Shamit K.
AU - Wang, Enfeng
AU - Gunosewoyo, Hendra
AU - Kozikowski, Alan P.
AU - Billadeau, Daniel D.
AU - Mukhopadhyay, Debabrata
PY - 2014/2
Y1 - 2014/2
N2 - 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.
AB - 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.
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U2 - 10.1158/1535-7163.MCT-13-0681
DO - 10.1158/1535-7163.MCT-13-0681
M3 - Article
C2 - 24327518
AN - SCOPUS:84894218696
SN - 1535-7163
VL - 13
SP - 285
EP - 296
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 2
ER -