Bortezomib Congeners Induce Apoptosis of Hepatocellular Carcinoma via CIP2A Inhibition

Hou, Duen Ren; Huang, Ann Chi; Shiau, Chung Wai; Wang, Chun Yi; Yu, Hui; Chen, Kuen Feng

doi:10.3390/molecules181215398

Cited by 9 publications

(6 citation statements)

References 12 publications

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“…First, cancer cells which exhibited equal proteasomal inhibition displayed a differential apoptotic response to Bortezomib (Chen et al, 2008; Liu et al, 2013; Tseng et al, 2012). Second, Bortezomib derivatives with diminished proteasomal inhibition showed equal or increased cytotoxicity to cancer cells (Hou et al, 2013). Additional evidence suggested that this secondary mechanism of action was through a loss of CIP2A expression in multiple cancer types (hepatocellular carcinoma, head and neck squamous cell carcinoma, triple negative breast cancer, and a variety of leukemias), resulting in increased PP2A activity (Chen et al, 2010; Ding et al, 2014; Hou et al, 2013; Lin et al, 2012; Liu et al, 2013) (Figure 3A).…”

Section: Targeting the Pp2a Inhibitor Cip2amentioning

confidence: 99%

“…Second, Bortezomib derivatives with diminished proteasomal inhibition showed equal or increased cytotoxicity to cancer cells (Hou et al, 2013). Additional evidence suggested that this secondary mechanism of action was through a loss of CIP2A expression in multiple cancer types (hepatocellular carcinoma, head and neck squamous cell carcinoma, triple negative breast cancer, and a variety of leukemias), resulting in increased PP2A activity (Chen et al, 2010; Ding et al, 2014; Hou et al, 2013; Lin et al, 2012; Liu et al, 2013) (Figure 3A). Furthermore, Bortezomib’s cytotoxic function was blunted by siRNA mediated loss of PP2A-C subunit, supporting the role of PP2A in mediating Bortezomib-induced cytotoxicity (Lin et al, 2012).…”

Section: Targeting the Pp2a Inhibitor Cip2amentioning

confidence: 99%

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Therapeutic targeting of PP2A

O’Connor

Perl

Léonard

et al. 2018

The International Journal of Biochemistry & Cell Biology

160

148

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Protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase that regulates many cellular processes. Given the central role of PP2A in regulating diverse biological functions and its dysregulation in many diseases, including cancer, PP2A directed therapeutics have become of great interest. The main approaches leveraged thus far can be categorized as follows: 1) inhibiting endogenous inhibitors of PP2A, 2) targeted disruption of post translational modifications on PP2A subunits, or 3) direct targeting of PP2A. Additional 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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Section: Targeting the Pp2a Inhibitor Cip2amentioning

confidence: 99%

Section: Targeting the Pp2a Inhibitor Cip2amentioning

confidence: 99%

Therapeutic targeting of PP2A

O’Connor

Perl

Léonard

et al. 2018

The International Journal of Biochemistry & Cell Biology

160

148

View full text Add to dashboard Cite

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“…The antitumor activity of Bortezomib has been reported in a variety of human cancers with several described molecular mechanisms . Independent investigations have now identified CIP2A as a Bortezomib target in HCC, leukemias, head and neck squamous cell carcinomas (HNSCC), triple negative breast carcinomas and colon cancers . CIP2A expression has been suggested to be the major determinant for mediating Bortezomib induced apoptosis in these cancers.…”

Section: Role Of Cip2a As a Biomarker For Anticancer Drugsmentioning

confidence: 99%

Clinical significance of cancerous inhibitor of protein phosphatase 2A in human cancers

Khanna

Pimanda

2015

Intl Journal of Cancer

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Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A), a recently identified oncogene, has emerged as a potential drug target for a range of different tumor types. High CIP2A expression has been reported in almost all solid organ cancers and in some hematological tumors and is associated with high grade and poor prognosis. Notably, high CIP2A expression is determined in over 70% of tumor patient samples in the majority of human cancers. High expression of CIP2A has also been proposed as a useful biomarker that predicts therapeutic response to chemotherapeutics such as Bortezomib, Erlotinib, Checkpoint Kinase 1 inhibitors and pro‐senescence based therapies. In this review, we highlight, critically evaluate and discuss the ambiguity in CIP2A's prognostic role in different human cancers and its role in modulating response and resistance to chemotherapeutics.

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“…CIP2A gene polymorphisms and hepatocellular carcinoma susceptibility has been reported [ 73 ]. Bortezomib (a proteosome inhibitor used in clinics on myeloma patients) congeners induced apoptosis in hepatocellular carcinoma cells via CIP2A inhibition [ 90 ]. The inhibition of CIP2A has been shown to determine the effect of bortezomib on apoptosis and PP2A-dependent AKT inactivation in hepatocellular carcinoma indicating that CIP2A may be a biomarker for predicting clinical response of bortezomib in hepatocellular carcinoma treatment [ 91 ].…”

Section: Introductionmentioning

confidence: 99%

Oncogenic nexus of cancerous inhibitor of protein phosphatase 2A (CIP2A): An oncoprotein with many hands

Carlson

Leyland‐Jones

et al. 2014

Oncotarget

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Oncoprotein CIP2A a Cancerous Inhibitor of PP2A forms an “oncogenic nexus” by virtue of its control on PP2A and MYC stabilization in cancer cells. The expression and prognostic function of CIP2A in different solid tumors including colorectal carcinoma, head & neck cancers, gastric cancers, lung carcinoma, cholangiocarcinoma, esophageal cancers, pancreatic carcinoma, brain cancers, breast carcinoma, bladder cancers, ovarian carcinoma, renal cell carcinomas, tongue cancers, cervical carcinoma, prostate cancers, and oral carcinoma as well as a number of hematological malignancies are just beginning to emerge. Herein, we reviewed the recent progress in our understanding of (1) how an “oncogenic nexus” of CIP2A participates in the tumorigenic transformation of cells and (2) how we can prospect/view the clinical relevance of CIP2A in the context of cancer therapy. The review will try to understand the role of CIP2A (a) as a biomarker in cancers and evaluate the prognostic value of CIP2A in different cancers (b) as a therapeutic target in cancers and (c) in drug response and developing chemo-resistance in cancers.

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Bortezomib Congeners Induce Apoptosis of Hepatocellular Carcinoma via CIP2A Inhibition

Cited by 9 publications

References 12 publications

Therapeutic targeting of PP2A

Therapeutic targeting of PP2A

Clinical significance of cancerous inhibitor of protein phosphatase 2A in human cancers

Oncogenic nexus of cancerous inhibitor of protein phosphatase 2A (CIP2A): An oncoprotein with many hands

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