Inhibition of protein phosphatase 2A with the small molecule LB100 overcomes cell cycle arrest in osteosarcoma after cisplatin treatment

Zhang, Chao; Hong, Christopher S.; Hu, Xu; Yang, Chunzhang; Wang, Herui; Zhu, Dongwang; Moon, Seogin; Dmitriev, Pauline; Lü, Jie; Chiang, Jeffrey; Zhuang, Zhengping; Zhou, Yue

doi:10.1080/15384101.2015.1041693

Cited by 25 publications

(24 citation statements)

References 30 publications

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“…LB-102 inhibits PP2A to increase the efficacy of drugs, including doxorubicin, in xenograph animal models of glioblastoma by blocking cellular DNA damage defence mechanisms that are targeted by the chemotherapeutic agent [37]. The related PP2A inhibitor, LB-100 (currently in clinical trials; NCT01837667 [56]), similarly enhances chemo-sensitivity to drugs in a number of cancer cell types, including sarcoma [57], pheochromocytoma [58], nasopharyngeal carcinoma [59], hepatocellular carcinoma [60], medulloblastoma [61] and pancreatic cancer [62,63] as well as both breast [64] and ovarian cancers [65].…”

Section: Discussionmentioning

confidence: 99%

RACK1 stabilises the activity of PP2A to regulate the transformed phenotype in mammary epithelial cells

Kiely

Adams

Hayes

et al. 2017

Cellular Signalling

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. (2017) RACK1 stabilises the activity of PP2A to regulate the transformed phenotype in mammary epithelial cells. Cellular Signalling, 35, pp. 290-300. (doi:10.1016Signalling, 35, pp. 290-300. (doi:10. /j.cellsig.2016 This is the author's final accepted version.There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.http://eprints.gla.ac.uk/128660/ RACK1/PP2A complex is required for cell adhesion, proliferation, migration, invasion.Potential role for the RACK1/PP2A complex in the progression of breast cancer. KeywordsBreast Cancer, RACK1, PP2A, Protein-Protein Interactions. ABSTRACTConflicting reports implicate the scaffolding protein RACK1 in the progression of breast cancer. RACK1 has been identified as a key regulator downstream of growth factor and adhesion signalling and as a direct binding partner of PP2A. Our objective was to further characterise the interaction between PP2A and RACK1 and to advance our understanding of this complex in breast cancer cells. We examined how the PP2A holoenzyme is assembled on the RACK1 scaffold in MCF-7 cells. We used immobilized peptide arrays representing the entire PP2A-catalytic subunit to identify candidate amino acids on the C subunit of PP2A that might be involved in binding of RACK1. We identified the RACK1 interaction sites on PP2A. Stable cell lines expressing PP2A with FR69/70AA, R214A and Y218F substitutions were generated and it was confirmed that the RACK1/PP2A interaction is essential to stabilize PP2A activity. We used Real-Time Cell Analysis and a series of assays to demonstrate that disruption of the RACK1/PP2A complex also reduces the adhesion, proliferation, migration and invasion of breast cancer cells and plays a role in maintenance of the cancer phenotype. This work has significantly advanced our understanding of the RACK1/PP2A complex and suggests a pro-carcinogenic role for the RACK1/PP2A interaction. This work suggests that approaches to target the RACK1/PP2A complex are a viable option to regulate PP2A activity and identifies a novel potential therapeutic target in the treatment of breast cancer.

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Section: Discussionmentioning

confidence: 99%

RACK1 stabilises the activity of PP2A to regulate the transformed phenotype in mammary epithelial cells

Kiely

Adams

Hayes

et al. 2017

Cellular Signalling

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“…In aggregate, research reports provide a largely consistent picture of the signaling mechanisms that underlie increased cytotoxin efficacy with LB100 adjuvant therapy: (1) AKT1 and MDM2 are activated while p53 is inhibited to prevent checkpoint activation in G1/S [84, 95, 96]. (2) Hyperphosphorylated PLK1 is activated and inhibits Chk1/2, which is no longer able to inhibit CDK1 and trigger G2 arrest [84, 95-98]. (3) This is compounded by removal of PP2A inhibition of CDC25c, which is also able to maintain CDK1 activity via de-phosphorylation.…”

Section: Pp2a Inhibitionmentioning

confidence: 99%

“…Cells progress to mitosis, but spindle formation is disordered and mitotic catastrophe occurs [84, 95, 96, 98, 99]. Disrupted cell cycle progression was further evident in cell cycle spread analyses, where treatment with a DNA damage inducer led to predominant S-phase arrest (more cells in G1/S), but when combined with PP2A inhibition by LB100, cells progress through S-phase and accumulated in G2/M due to disordered mitosis [84, 95, 96, 98-100]. PLK1 inhibition of TCTP, a protein that stabilizes microtubules and has anti-apoptotic functions, may contribute to abnormal mitotic figures and mitotic catastrophe [84, 96].…”

Section: Pp2a Inhibitionmentioning

confidence: 99%

Targeting PP2A in cancer: Combination therapies

Mazhar¹,

Taylor²,

Sangodkar³

et al. 2019

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

110

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The serine/threonine phosphatase PP2A regulates a vast portion of the phosphoproteome including pathways involved in apoptosis, proliferation and DNA damage response and PP2A inactivation is a vital step in malignant transformation. Many groups have explored the therapeutic venue of combining PP2A reactivation with kinase inhibition to counteract the very changes in tumor suppressors and oncogenes that lead to cancer development. Conversely, inhibition of PP2A to complement chemotherapy and radiation-induced cancer cell death is also an area of active investigation. Here we review the studies that utilize PP2A targeted agents as combination therapy in cancer. A potential role for PP2A in tumor immunity is also highlighted.

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“…Cisplatin [also known as diamminedichloridoplatinum (II) (DDP)] is commonly used for the clinical treatment of OS (3,4). However, treatment with DDP may induce tumor chemotherapy resistance (5). Although the underlying molecular mechanism has not been fully uncovered yet, it has been demonstrated that the activation of autophagy plays a key role in DDP-induced chemotherapy resistance (6).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-199a-5p inhibits cisplatin-induced drug resistance via inhibition of autophagy in osteosarcoma cells

Jiang

et al. 2016

Oncology Letters

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Abstract. Osteosarcoma (OS) is the most common cancer of the bone. Chemotherapy is commonly used for the clinical treatment of OS. However, chemoresistance to cisplatin [also known as diamminedichloridoplatinum (II) (DDP)] is a major obstacle for OS therapy, the underlying mechanism of which is not fully understood. The present study aimed to investigate the role of microRNA (miR)-199a-5p in the regulation of chemoresistance to DDP in OS cells. Reverse transcription-quantitative polymerase chain reaction demonstrated that the expression level of miR-199a-5p was significantly reduced in human OS MG63 cells. In addition, DDP treatment also upregulated the protein levels of light chain 3 (LC3)-II and Beclin1 as well as the ratio of LC3-II vs. LC3-I in MG63 cells, indicating that autophagy was activated. Restoration of miR-199a-5p expression promoted DDP-induced inhibition of MG63 cell proliferation and inhibited DDP-induced autophagy, as indicated by the reduced protein levels of LC3-II and Beclin1 and the ratio of LC3-II vs. LC3-I. Finally, luciferase reporter assay data revealed that miR-199a-5p directly targeted Beclin1 and negatively mediated Beclin1 expression at a post-transcriptional level in MG63 cells. In conclusion, our study suggests that miR-199a-5p promotes the cytotoxicity of DDP in OS cells via inhibition of autophagy. Therefore, miR-199a-5p/autophagy signaling is involved in chemoresistance and may become a potential target for the treatment of DDP-resistant OS.

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Inhibition of protein phosphatase 2A with the small molecule LB100 overcomes cell cycle arrest in osteosarcoma after cisplatin treatment

Cited by 25 publications

References 30 publications

RACK1 stabilises the activity of PP2A to regulate the transformed phenotype in mammary epithelial cells

RACK1 stabilises the activity of PP2A to regulate the transformed phenotype in mammary epithelial cells

Targeting PP2A in cancer: Combination therapies

MicroRNA-199a-5p inhibits cisplatin-induced drug resistance via inhibition of autophagy in osteosarcoma cells

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