Cancerous inhibitor of PP2A is targeted by natural compound celastrol for degradation in non-small-cell lung cancer

Li, Zi; Ma, Liang; Wen, Zhesheng; Hu, Zheng; Wu, Fuqun; Li, Wei; Liu, Jinsong; Zhou, Guang‐Biao

doi:10.1093/carcin/bgt395

Cited by 94 publications

(92 citation statements)

References 53 publications

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“…In addition, the invasive behavior of MDA-MB-231 cells was examined by CIP2A small interfering (si)siRNA, and found that CIP2A depletion inhibits the invasion and migration of MDA-MB-231. Previously, CIP2A has been shown to be an oncoprotein capable of modulating phosphorylated-Akt (pAkt) (9,12). Results of the present study demonstrated that CIP2A depletion inhibits phosphorylation of Akt and its downstream molecules, mechanistic target of rapamycin (mTOR) and p70 ribosomal protein S6 kinase (P70S6K).…”

Section: Introductionmentioning

confidence: 47%

“…Recently, CIP2A expression has been found to be associated with the invasive function of breast cancer (10). Based on the role of CIP2A in stabilizing and upregulating the c-Myc oncoprotein, previous reports found that c-Myc is involved in CIP2A-stimulated invasiveness of tumor cells (3,9,10). The expression of c-Myc was analyzed by western blot, and it was observed that c-Myc is downregulated by CIP2A depletion.…”

Section: A B C Discussionmentioning

confidence: 99%

“…CIP2A is a widespread oncogenic factor in human neoplasms (4)(5)(6)(7)(8)(9)3). Similar to the Ras oncogene, CIP2A is required for anchorage-independent cell growth and malignant transformation of human cells (4).…”

Section: A B C Discussionmentioning

confidence: 99%

“…Previous studies have shown that CIP2A serves a critical role in the progression of several cancer types, including head and neck squamous cell carcinoma, oral squamous cell carcinoma, oesophageal squamous cell carcinoma, colon, gastric, breast, prostate, tongue, lung, cervical cancer and acute myeloid leukaemia (3)(4)(5)(6)(7)(8)(9). In 2009, Côme et al (10) demonstrated that CIP2A is associated with clinical aggressivity in human breast cancer and promotes the malignant growth of breast cancer cells (10).…”

Section: Introductionmentioning

confidence: 99%

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Expression of cancerous inhibitor of protein phosphatase 2A in human triple negative breast cancer correlates with tumor survival, invasion and autophagy

Feng

Guo

et al. 2016

Oncology Letters

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Abstract. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently characterized oncoprotein which is involved in the progression of several human malignancies. The present study aimed to investigate its biological function in human triple negative breast cancer (TNBC). The expression of CIP2A in TNBC cells was examined and it was observed that CIP2A was elevated in the TNBC cell line compared with poorly invasive breast cancer cells. CIP2A depletion in TNBC cell lines inhibited proliferation, and induced apoptosis and autophagy. In addition, CIP2A depletion inhibited invasion and migration of TNBC cells. Furthermore, CIP2A depletion downregulated Akt/mTOR/P70S6K phosphorylation. These results validate the role of CIP2A as a invasion-associated oncoprotein and established CIP2A as a promising therapeutic target of TNBC.

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Section: Introductionmentioning

confidence: 47%

Section: A B C Discussionmentioning

confidence: 99%

Section: A B C Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Expression of cancerous inhibitor of protein phosphatase 2A in human triple negative breast cancer correlates with tumor survival, invasion and autophagy

Feng

Guo

et al. 2016

Oncology Letters

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“…These compounds had the following IC 50 values in FPPS inhibition: compound 9:, TbFPPS, 17 μM and HsFPPS, no activity; compound 10: TbFPPS, 54 μM; HsFPPS, 81 μM (SI Appendix, Table S1). Both compounds are quinone methides, and compound 9 has diverse biological activities (30)(31)(32)(33). Therefore we elected to use compound 9 as the basis for a similarity search using the NCI/ DTP option in PubChem (https://pubchem.ncbi.nlm.nih.gov/) with compounds again being obtained from the NCI/DTP (http://dtp.…”

Section: Resultsmentioning

confidence: 99%

Taxodione and arenarone inhibit farnesyl diphosphate synthase by binding to the isopentenyl diphosphate site

Liu¹,

Lindert

Zhu³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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We used in silico methods to screen a library of 1,013 compounds for possible binding to the allosteric site in farnesyl diphosphate synthase (FPPS). Two of the 50 predicted hits had activity against either human FPPS (HsFPPS) or Trypanosoma brucei FPPS (TbFPPS), the most active being the quinone methide celastrol (IC 50 versus TbFPPS ∼20 μM). Two rounds of similarity searching and activity testing then resulted in three leads that were active against HsFPPS with IC 50 values in the range of ∼1-3 μM (as compared with ∼0.5 μM for the bisphosphonate inhibitor, zoledronate). The three leads were the quinone methides taxodone and taxodione and the quinone arenarone, compounds with known antibacterial and/or antitumor activity. We then obtained X-ray crystal structures of HsFPPS with taxodione+zoledronate, arenarone+zoledronate, and taxodione alone. In the zoledronate-containing structures, taxodione and arenarone bound solely to the homoallylic (isopentenyl diphosphate, IPP) site, not to the allosteric site, whereas zoledronate bound via Mg 2+ to the same site as seen in other bisphosphonate-containing structures. In the taxodione-alone structure, one taxodione bound to the same site as seen in the taxodione+zoledronate structure, but the second located to a more surface-exposed site. In differential scanning calorimetry experiments, taxodione and arenarone broadened the native-to-unfolded thermal transition (T m ), quite different to the large increases in ΔT m seen with biphosphonate inhibitors. The results identify new classes of FPPS inhibitors, diterpenoids and sesquiterpenoids, that bind to the IPP site and may be of interest as anticancer and antiinfective drug leads.prenyl synthase | crystallography | prenylation | molecular dynamics | drug discovery F arnesyl diphosphate synthase (FPPS) catalyzes the condensation of isopentenyl diphosphate (IPP; compound 1 in Fig. 1) with dimethylallyl diphosphate (DMAPP; compound 2 in Fig. 1) to form the C 10 isoprenoid geranyl diphosphate (GPP; compound 3 in Fig. 1), which then condenses with a second IPP to form the C 15 isoprenoid, farnesyl diphosphate (FPP; compound 4 in Fig. 1). FPP then is used in a wide range of reactions including the formation of geranylgeranyl diphosphate (GGPP) (1), squalene (involved in cholesterol and ergosterol biosynthesis), dehydrosqualene (used in formation of the Staphylococcus aureus virulence factor staphyloxanthin) (2), undecaprenyl diphosphate (used in bacterial cell wall biosynthesis), and quinone and in heme a/o biosynthesis. FPP and GGPP also are used in protein (e.g., Ras, Rho, Rac) prenylation, and FPPS is an important target for the bisphosphonate class of drugs (used to treat bone resorption diseases) such as zoledronate (compound 5 in Fig. 1) (3). Bisphosphonates targeting FPPS have activity as antiparasitics (4), act as immunomodulators (activating γδ T cells containing the Vγ2Vδ2 T-cell receptor) (5), and switch macrophages from an M2 (tumorpromoting) to an M1 (tumor-killing) phenotype (6). They also kill tumor cells (7) and...

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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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Cancerous inhibitor of PP2A is targeted by natural compound celastrol for degradation in non-small-cell lung cancer

Cited by 94 publications

References 53 publications

Expression of cancerous inhibitor of protein phosphatase 2A in human triple negative breast cancer correlates with tumor survival, invasion and autophagy

Expression of cancerous inhibitor of protein phosphatase 2A in human triple negative breast cancer correlates with tumor survival, invasion and autophagy

Taxodione and arenarone inhibit farnesyl diphosphate synthase by binding to the isopentenyl diphosphate site

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

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