Bortezomib Sensitizes HCC Cells to CS-1008, an Antihuman Death Receptor 5 Antibody, through the Inhibition of CIP2A
Kuen-Feng Chen,Hui Chuan Yu,Chun Yu Liu,Hui Ju Chen,Yi Ching Chen,Duen Ren Hou,Pei-Jer Chen,Ann-Lii Cheng +7 more
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TLDR
It is reported that bortezomib sensitized HCC cells to CS-1008 through the inhibition of CIP2A, and in vivo data showed that CS- 1008 and bortzomib combination treatment decreased tumor growth significantly.Abstract:
Previously, we have shown that bortezomib overcame TRAIL resistance in hepatocellular carcinoma (HCC) cells via the inhibition of Akt. Here, we report that bortezomib sensitizes these TRAIL-resistant cells, including Huh-7, Hep3B, and Sk-Hep1, to CS-1008, a humanized agonistic antihuman death receptor 5 antibody. Cancerous inhibitor of protein phosphatase 2A (CIP2A) mediated the sensitizing effect of bortezomib to CS-1008 through inhibiting protein phosphatase 2A (PP2A) activity. Combination treatment of bortezomib and CS-1008 downregulated CIP2A in a concentration- and time-dependent manner, and increased PP2A activity in HCC cells. Importantly, ectopic expression of CIP2A decreased Akt-related PP2A activity, indicating that CIP2A negatively regulates Akt-related PP2A activity in HCC cells. Moreover, silencing CIP2A by short interfering RNA enhanced CS-1008-induced apoptosis in HCC cells and ectopic expression of CIP2A in HCC cells abolished CS-1008-induced apoptosis, indicating that CIP2A plays an important role in the sensitizing effect of bortezomib to CS-1008. Finally, our in vivo data showed that CS-1008 and bortezomib combination treatment decreased tumor growth significantly. In conclusion, bortezomib sensitized HCC cells to CS-1008 through the inhibition of CIP2A.read more
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Therapeutic targeting of PP2A.
TL;DR: Insight into the structural, molecular, and biological framework driving the efficacy of these therapeutic strategies will provide a foundation for the refinement and development of novel and clinically tractable PP2A targeted therapies.
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Dovitinib Induces Apoptosis and Overcomes Sorafenib Resistance in Hepatocellular Carcinoma through SHP-1–Mediated Inhibition of STAT3
Wei Tien Tai,Ann-Lii Cheng,Chung Wai Shiau,Chunyu Liu,Ching Huai Ko,Mai Wei Lin,Pei-Jer Chen,Kuen-Feng Chen +7 more
TL;DR: Dovitinib induces significant apoptosis in HCC cells and sorafenib-resistant cells via SHP-1–mediated inhibition of STAT3, suggesting that targeting STAT3 may be a useful approach to overcome drug resistance in H CC.
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CIP2A is a target of bortezomib in human triple negative breast cancer cells
Ling Ming Tseng,Chunyu Liu,Chunyu Liu,Kung-Chi Chang,Kung-Chi Chang,Pei-Yi Chu,Chung Wai Shiau,Kuen-Feng Chen +7 more
TL;DR: CIP2A is a major determinant mediating bortezomib-induced apoptosis in TNBC cells and may be a potential therapeutic target in T NBC, which currently has no specific therapeutic targets.
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Challenges and Opportunities in the Development of Protein Phosphatase-Directed Therapeutics
TL;DR: Strategies for the development of activators and inhibitors of protein phosphatases are described and some long-standing misconceptions concerning the druggability of these enzymes are clarified.
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The role and therapeutic potential of Ser/Thr phosphatase PP2A in apoptotic signalling networks in human cancer cells.
Veerle Janssens,Angelita Rebollo +1 more
TL;DR: Current knowledge about the regulatory functions of Protein Phosphatase type 2A (PP2A) phosphatases in these apoptotic signalling networks are reviewed and it is speculated how this knowledge might be exploited for therapeutic purposes, in light of pre-clinical pharmacological approaches currently demonstrated to target PP2A in cancer cells.
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