Activation of protein phosphatase 2A tumor suppressor as potential treatment of pancreatic cancer

Chien, Wenwen; Sun, Qiao-Yang; Lee, Kian Leong; Ding, Ling-Wen; Wuensche, Peer; Torres-Fernandez, Lucia A.; Tan, Siew Zhuan; Tokatly, Itay; Zaiden, Norazean; Poellinger, Lorenz; Mori, Seiichi; Yang, Henry; Tyner, Jeffrey W.; Koeffler, H. Phillip

doi:10.1016/j.molonc.2015.01.002

Cited by 80Pancreatic and Hepatic Oncology ResearchProtein Tyrosine PhosphatasesProtein Kinase Regulation and GTPase Signaling

Activation of protein phosphatase 2A tumor suppressor as potential treatment of pancreatic cancer

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Chien, Wenwen, Sun, Qiao-Yang, Lee, Kian Leong, Ding, Ling-Wen, Wuensche, Peer, Torres-Fernandez, Lucia A., Tan, Siew Zhuan, Tokatly, Itay +6 more·2015·Molecular Oncology

DOI 10.1016/j.molonc.2015.01.002PMC PMC4387089

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Abstract

We utilized three tiers of screening to identify novel therapeutic agents for pancreatic cancers. First, we analyzed 14 pancreatic cancer cell lines against a panel of 66 small-molecule kinase inhibitors and dasatinib was the most potent. Second, we performed RNA expression analysis on 3 dasatinib-resistant and 3 dasatinib-sensitive pancreatic cancer cell lines to profile their gene expression. Third, gene profiling data was integrated with the Connectivity Map database to search for potential drugs. Thioridazine was one of the top ranking small molecules with highly negative enrichment. Thioridazine and its family members of phenothiazine including penfluridol caused pancreatic cancer cell death and affected protein expression levels of molecules involved in cell cycle regulation, apoptosis, and multiple kinase activities. This family of drugs causes activation of protein phosphatase 2 (PP2A). The drug FTY-720 (activator of PP2A) induced apoptosis of pancreatic cancer cells. Silencing catalytic unit of PP2A rendered pancreatic cancer cells resistant to penfluridol. Our observations suggest potential therapeutic use of penfluridol or similar agent associated with activation of PP2A in pancreatic cancers.

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Thioridazine diminished phosphorylated GSK3β and MCL-1 levels when combined with metformin.
“Thioridazine, another PP2A activator (Chien et al., 2015) that we found to diminish phosphorylated GSK3 b and MCL-1 levels when combined with metformin (Figure S5B)”
From Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis (2019) · cites this paper as Chien et al., 2015

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Senapedis W Landesman Y Pursell N Crochiere M McCauley D Ellis J Kashyap T Klebanov B Carlson R Kalid O Kauffman M Shacham S Baloglu E 2014 Novel Selective Orally Bioavailable Small Molecule PAK4 Allosteric Modulators Display Anti-Tumor Activity and Induce Apoptosis In Vitro and In Vivo Proceedings of the Annual Meeting of the American Association for Cancer Research 2014 Apr 5–9 2014 San Diego, CA AACR 2014 Abstract nr 748

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BackgroundResultInfluential
Regulation of the phosphoprotein phosphatase 2A system and its modulation during oxidative stress: A potential therapeutic target?
Elgenaidi, I. S., & Spiers, P. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.02.011 · Cited by 65 · see citing works
Penfluridol suppresses glioblastoma tumor growth by Akt-mediated inhibition of GLI1
Ranjan, A., & Srivastava, S. (2017) · Oncotarget · doi:10.18632/oncotarget.16515 · Cited by 57 · see citing works
“in pancreatic cancer cells with IC50 ranging from 9–37 μM [19] while our current studies showed much lower IC50 in glioblastoma cells ranging 3–5 μM only.”
Background
Repurposing Antipsychotics for Cancer Treatment
Vlachos, N., Lampros, M. G., Voulgaris, S., & Alexiou, G. Α. (2021) · Biomedicines · doi:10.3390/biomedicines9121785 · Cited by 50 · see citing works
“, Bcl-2), indicating an apoptotic-mediated pathway of cell death [82].”
Background
In vitro anticancer activity of fluphenazine, perphenazine and prochlorperazine. A review
Otręba, M., & Kośmider, L. (2020) · Journal of Applied Toxicology · doi:10.1002/jat.4046 · Cited by 50 · see citing works
Penfluridol triggers cytoprotective autophagy and cellular apoptosis through ROS induction and activation of the PP2A-modulated MAPK pathway in acute myeloid leukemia with different FLT3 statuses
Wu, S., Wen, Y.-C., Ku, C., Yang, Y.-C., Chow, J., Yang, S.-F., Lee, W.-J., & Chien, M. (2019) · Journal of Biomedical Science · doi:10.1186/s12929-019-0557-2 · Cited by 47 · see citing works
Penfluridol as a Candidate of Drug Repurposing for Anticancer Agent
Nguyen, T. M., & Lee, C. H. (2019) · Molecules · doi:10.3390/molecules24203659 · Cited by 45 · see citing works
“In another study, cyclin D and Myc, which are associated with cell growth, were inhibited by penfluridol [15] (Figure 3).”
BackgroundInfluential
A chemogenomic screening identifies CK2 as a target for pro-senescence therapy in PTEN-deficient tumours
Kalathur, M., Toso, A., Chen, J., Revandkar, A., Danzer-Baltzer, C., Guccini, I., Alajati, A., Sarti, M., Pinton, S., Brambilla, L., et al. (2015) · Nature Communications · doi:10.1038/ncomms8227 · Cited by 44 · see citing works
Ion Channels as Therapeutic Targets in High Grade Gliomas
Griffin, M., Khan, R. N., Basu, S., & Smith, S. J. (2020) · Cancers · doi:10.3390/cancers12103068 · Cited by 44 · see citing works
“The efficacy of repurposing calcium channel blockers has also been demonstrated in other cancers; pimozide and penfluridol are effective in decreasing the viability in retinoblastoma and breast cancer cells [135] and disrupts cell cycle activity in pancreatic cancer cell lines [136].”
Background
In�silico analysis identified miRNA‑based therapeutic agents against glioblastoma multiforme
Xiong, D., Xu, W., He, R., Dang, Y., Chen, G., & Luo, D. (2019) · Oncology Reports · doi:10.3892/or.2019.7022 · Cited by 40 · see citing works
Drug Repurposing, an Attractive Strategy in Pancreatic Cancer Treatment: Preclinical and Clinical Updates
De Lellis, L., Veschi, S., Tinari, N., Mokini, Z., Carradori, S., Brocco, D., Florio, R., Grassadonia, A., & Cama, A. (2021) · Cancers · doi:10.3390/cancers13163946 · Cited by 40 · see citing works
“Auranofin Rheumatoid arthritis In vitro/ animal models Inhibition of TrxR1 and HIF1α leading to decreased antioxidant activity within PC cells, followed by apoptosis; antitumor effect at the primary site and suppression of distant organ metastasis in PC orthotopic mouse models [20] In vitro/ animal models Preferential…”
BackgroundInfluential
Protein phosphatase 2A-B55δ enhances chemotherapy sensitivity of human hepatocellular carcinoma under the regulation of microRNA-133b
Zhuang, Q., Zhou, T., He, C., Zhang, S., Qiu, Y., Luo, B., Zhao, R., Liu, H., Lin, Y., & Lin, Z. (2016) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-016-0341-z · Cited by 38 · see citing works
“reported that PP2A activation is crucial for deceleration of pancreatic tumorigenesis [24].”
Background
Functional Genome-wide Screening Identifies Targets and Pathways Sensitizing Pancreatic Cancer Cells to Dasatinib
Chien, W., Sudo, M., Ding, L., Sun, Q., Wuensche, P., Lee, K. L., Hattori, N., Garg, M., Xu, L., Zheng, Y., et al. (2018) · Journal of Cancer · doi:10.7150/jca.25138 · Cited by 38 · see citing works
“We previously identified dasatinib-sensitive and -resistant pancreatic cancer cell lines [13].”
Background
Autophagosome accumulation-mediated ATP energy deprivation induced by penfluridol triggers nonapoptotic cell death of lung cancer via activating unfolded protein response
Hung, W.-Y., Chang, J., Cheng, Y. W., Cheng, G.-Z., Huang, H.-C., Hsiao, M., Chung, C., Lee, W.-J., & Chien, M. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1785-9 · Cited by 37 · see citing works
Treatment of cancer with antipsychotic medications: Pushing the boundaries of schizophrenia and cancer
Brown, J. S. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.104809 · Cited by 33 · see citing works
Penfluridol induces endoplasmic reticulum stress leading to autophagy in pancreatic cancer
Ranjan, A., German, N., Mikelis, C. M., Srivenugopal, K. S., & Srivastava, S. (2017) · Tumor Biology · doi:10.1177/1010428317705517 · Cited by 33 · see citing works
Potential anti-tumor effects of FTY720 associated with PP2A activation: a brief review
Cristóbal, I., Madoz‐Gúrpide, J., Manso, R., Gónzález-Alonso, P., Rojo, F., & García‐Foncillas, J. (2016) · Current Medical Research and Opinion · doi:10.1185/03007995.2016.1162774 · Cited by 29 · see citing works
Disruption and inactivation of the PP2A complex promotes the proliferation and angiogenesis of hemangioma endothelial cells through activating AKT and ERK
Xie, F., Bao, X., Yu, J., Chen, W., Wang, L., Zhang, Z., & Xu, Q. (2015) · Oncotarget · doi:10.18632/oncotarget.4705 · Cited by 28 · see citing works
“These observations implicate PP2A as a potential tumor suppressor [20, 21].”
Drug Repurposing Opportunities in Pancreatic Ductal Adenocarcinoma
Rebelo, R., Polónia, B. R. G., Santos, L. L., Vasconcelos, M. H., & Xavier, C. P. R. (2021) · Pharmaceuticals · doi:10.3390/ph14030280 · Cited by 28 · see citing works
“Drug Pharmacological Class Original Indication Evidence Biological Models Tested Concentrations Described Mechanisms References In Vitro In Vivo Clinical Carglumic acid Amino acids andderivatives Hyperammonemia + + • Human (AsPC-1 and Capan-1) and Murine (Pan02) pancreatic cancer cell lines • Human pancreatic ductal e…”
BackgroundInfluential
Drug repurposing: Antimicrobial and antibiofilm effects of penfluridol against Enterococcus faecalis
Zeng, X., She, P., Zhou, L., Li, S., Hussain, Z. B., Chen, L., & Wu, Y. C. (2020) · MicrobiologyOpen · doi:10.1002/mbo3.1148 · Cited by 23 · see citing works
KLF14 regulates the growth of hepatocellular carcinoma cells via its modulation of iron homeostasis through the repression of iron-responsive element-binding protein 2
Zhou, H., Chen, J., Fan, M., Cai, H., Dong, Y., Qiu, Y., Zhuang, Q., Lei, Z., Li, M., Ding, X., et al. (2023) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-022-02562-4 · Cited by 23 · see citing works
Pre-Clinical Study Evaluating Novel Protein Phosphatase 2A Activators as Therapeutics for Neuroblastoma
Bownes, L. V., Marayati, R., Quinn, C. H., Beierle, A. M., Hutchins, S. C., Julson, J. R., Erwin, M. H., Stewart, J. E., Mroczek‐Musulman, E., Ohlmeyer, M. H. J., et al. (2022) · Cancers · doi:10.3390/cancers14081952 · Cited by 20 · see citing works
“Similarly, synergy was found between FTY720 and the RTK/SRC/TEC inhibitor dasatinib in inhibiting pancreatic cancer proliferation [27].”
Background
Upregulation of PP2Ac predicts poor prognosis and contributes to aggressiveness in hepatocellular carcinoma
Gong, S.-J., Feng, X., Song, W., Chen, J., Wang, S., Xing, D.-J., Zhu, M.-H., Zhang, S., & Xu, A.-M. (2015) · Cancer Biology & Therapy · doi:10.1080/15384047.2015.1121345 · Cited by 20 · see citing works
Phosphatases and solid tumors: focus on glioblastoma initiation, progression and recurrences
Dedobbeleer, M., Willems, E., Freeman, S. D., Lombard, A., Goffart, N., & Rogister, B. (2017) · Biochemical Journal · doi:10.1042/bcj20170112 · Cited by 19 · see citing works
Identification of Metastasis-Associated MicroRNAs in Metastatic Melanoma by miRNA Expression Profile and Experimental Validation
Gao, Y., Xu, J., Li, H., Hu, Y., & Yu, G. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.663110 · Cited by 19 · see citing works
“Recently, microarray technology has been widely used in investigating gene alterations in metastasis, tumorigenesis, drug resistance, and cancer recurrence, as well as to identify biomarkers for tumor diagnosis, prognosis, and therapy (Hu et al., 2010; Chien et al., 2015; Tabaries et al., 2015).”
Non-immunosuppressive triazole-based small molecule induces anticancer activity against human hormone-refractory prostate cancers: the role in inhibition of PI3K/AKT/mTOR and c-Myc signaling pathways
Leu, W., Swain, S. P., Chan, S.-H., Hsu, J., Liu, S., Chan, M.-L., Yu, C.-C., Hsu, L., Chou, Y.-L., Chang, W.-L., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.12765 · Cited by 18 · see citing works
“In recent decade, a considerable number of studies have been conducted on FTY720induced anticancer effect through diverse pathways, including inhibition of histone deacetylase [11], activation of protein phosphatase 2A [12], inhibition of STAT3 signaling [13], up-regulation of death receptor mediating signaling [14] a…”
Background
A Network Pharmacology-Based Analysis of Multi-Target, Multi-Pathway, Multi-Compound Treatment for Ovarian Serous Cystadenocarcinoma
Xiong, D., Qin, Y., Xu, W., He, R., Wu, H., Wei, D.-M., Zeng, J., Dang, Y., & Chen, G. (2018) · Clinical Drug Investigation · doi:10.1007/s40261-018-0683-8 · Cited by 16 · see citing works
Leucine-Rich Repeat Kinase 2 Controls the Ca2+/Nuclear Factor of Activated T Cells/IL-2 Pathway during Aspergillus Non-Canonical Autophagy in Dendritic Cells
Wong, A. Y. W., Oikonomou, V., Paolicelli, G., LUCA, A. D., Pariano, M., Frič, J., Tay, H. S., Ricciardi‐Castagnoli, P., & Zelante, T. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00210 · Cited by 15 · see citing works
“PP2A has been implicated in meiosis and mitosis in numerous studies (47, 48) and is currently being explored as a treatment target for pancreatic cancer (49).”
Background
Upregulation of C1-inhibitor in pancreatic cancer
Osther, K., Förnvik, K., Liljedahl, E., Salford, L. G., & Redebrandt, H. N. (2019) · Oncotarget · doi:10.18632/oncotarget.27191 · Cited by 14 · see citing works
“com contrast to PP2A, which has been suggested to be a target to be activated in conjunction to therapies [7].”
BackgroundInfluential
Transcriptome analysis reveals PRKCA as a potential therapeutic target for overcoming cisplatin resistance in lung cancer through ferroptosis
Sun, T., Zhang, P., Zhang, Q., Wang, B., Zhao, Q., Liu, F., Ma, X., Zhao, C., Zhou, X., Chen, R., et al. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e30780 · Cited by 13 · see citing works
Human pancreatic cancer patients with Epithelial-to-Mesenchymal Transition and an aggressive phenotype show a disturbed balance in Protein Phosphatase Type 2A expression and functionality
van Pelt, J. F., Meeusen, B., Derua, R., Guffens, L., Cutsem, E. V., Janssens, V., & Verslype, C. (2023) · Journal of Translational Medicine · doi:10.1186/s12967-023-04145-z · Cited by 11 · see citing works
“Besides in PDAC [38, 68] some progress has already been achieved with these molecules in several treatmentresistant forms of cancer, including KRAS-mutant and TKI-resistant non-small cell lung cancer [37, 70], castration-resistant prostate cancer [71], endometrial cancer [72], leukemia [38, 73–75] and neuroblastoma [7…”
Background
Identification of Keratinocyte Differentiation-Involved Genes for Metastatic Melanoma by Gene Expression Profiles
Li, K., Guo, S., Tong, S., Sun, Q., Jin, S., Qi, B., Shao, Y., & Xu, N. (2021) · Computational and Mathematical Methods in Medicine · doi:10.1155/2021/9652768 · Cited by 11 · see citing works
PATHOME-Drug: a subpathway-based polypharmacology drug-repositioning method
Nam, S., Lee, S., Park, S., Lee, J., Park, A., Kim, Y. H., & Park, T. (2021) · Bioinformatics · doi:10.1093/bioinformatics/btab566 · Cited by 10 · see citing works
The Effects of Protein Phosphatase 2A Activation with Novel Tricyclic Sulfonamides on Hepatoblastoma
Bownes, L. V., Julson, J. R., Quinn, C. H., Hutchins, S. C., Erwin, M. H., Markert, H. R., Stewart, J. E., Mroczek‐Musulman, E., Aye, J. M., Yoon, K. J., et al. (2023) · Journal of Pediatric Surgery · doi:10.1016/j.jpedsurg.2023.02.017 · Cited by 9 · see citing works
Discovery of Turn-On Fluorescent Probes for Detecting PDEδ Protein in Living Cells and Tumor Slices
Dong, G., Chen, L., Zhang, J., Liu, T., Du, L., Sheng, C., & Li, M. (2020) · Analytical Chemistry · doi:10.1021/acs.analchem.0c00335 · Cited by 9 · see citing works
Screening common signaling pathways associated with drug resistance in non‐small cell lung cancer via gene expression profile analysis
Sun, T., Zhao, Q., Zhang, C., Cao, L., Song, M., Maimela, N. R., Liu, S., Wang, J., Gao, Q., Qin, G., et al. (2019) · Cancer Medicine · doi:10.1002/cam4.2190 · Cited by 8 · see citing works
Prediction and identification of synergistic compound combinations against pancreatic cancer cells
KalantarMotamedi, Y., Choi, R. J., Koh, S.-B., Bramhall, J. L., Fan, T.-P., & Bender, A. (2021) · iScience · doi:10.1016/j.isci.2021.103080 · Cited by 8 · see citing works
Penfluridol inhibits melanoma growth and metastasis through enhancing von Hippel‒Lindau tumor suppressor‐mediated cancerous inhibitor of protein phosphatase 2A (CIP2A) degradation
Xu, F., Li, J., Ai, M., Zhang, T., Ming, Y., Li, C., Pu, W., Yang, Y., Li, Z., Qi, Y., et al. (2024) · MedComm · doi:10.1002/mco2.758 · Cited by 6 · see citing works
Phosphatase Dysregulation in Cancer: Signaling Pathways and Therapeutic Opportunities
Jama, M., Overduin, M., & Barakat, K. (2025) · MedComm – Oncology · doi:10.1002/mog2.70028 · Cited by 7 · see citing works
Identification of biomarkers and their functions in dasatinib‑resistant pancreatic cancer using bioinformatics analysis
Wei, J., Han, R., Su, X., Chen, Y., Shi, J., Cui, X., Zhang, H., Gong, Y., Chu, X., & Chen, J. (2019) · Oncology Letters · doi:10.3892/ol.2019.10281 · Cited by 6 · see citing works
“Dasatinib is a potent receptor tyrosine kinase/Src inhibitor, which reduces pancreatic tumor cell growth in vitro (11).”
BackgroundMethodInfluential
Novel PP2A-Activating Compounds in Neuroblastoma
Nazam, N., Bownes, L. V., Julson, J. R., Quinn, C. H., Erwin, M. H., Marayati, R., Markert, H. R., Shirley, S., Stewart, J. E., Yoon, K. J., et al. (2024) · Cancers · doi:10.3390/cancers16223836 · Cited by 6 · see citing works
“PP2A reactivation has recently emerged as a medicinally tractable target for cancer therapeutics [12,13].”
Drug repositioning: examining antipsychotic drugs and their anticancer effects
Sagnak, A., & Arı, F. (2025) · DARU Journal of Pharmaceutical Sciences · doi:10.1007/s40199-025-00562-1 · Cited by 4 · see citing works
“The possibility of using several phenothiazines as a treatment for pancreatic cancer was investigated by Chien et al. (2015).”
Repurposing the antipsychotic drug penfluridol for cancer treatment (Review)
Mze, A. A. I., & Rahman, A. A. (2024) · Oncology Reports · doi:10.3892/or.2024.8833 · Cited by 4 · see citing works
“PF inhibited the proliferation and colony formation of pancreatic cancer cells (28‑31) through the suppression of prolactin receptor (PRLR) signalling (30) and the activation of protein phosphatase 2A (PP2A) protein phos‑ phatase (31).”
Background
Elements Identification in Golden Strawberries (Physalis Peruviana L.) using Wavelength Dispersive X-Ray Fluorescence
Akbaba, U. (2019) · Turkish Journal of Agriculture - Food Science and Technology · doi:10.24925/turjaf.v7i6.851-855.2386 · Cited by 4 · see citing works
Anticancer Properties of Antipsychotic Drugs
Borovčanin, M., Stojanović, B., Stojanovic, M. D., Stojanović, B., Lazovic, A., & Mitrović, M. M. (2024) · Interdisciplinary cancer research · doi:10.1007/16833_2024_394 · Cited by 3 · see citing works
Isolation of Primary Hepatocytes for Testing Tumor Penetrating Peptides
Savier, É., Tufféry, P., Bruzzoni‐Giovanelli, H., & Rebollo, A. (2021) · Methods in molecular biology · doi:10.1007/978-1-0716-1752-6_26 · Cited by 3 · see citing works
Protein phosphatase 2A as a therapeutic target in pancreatic cancer: past insights, recent advances, and future directions
Shah, V. M., & Sears, R. C. (2025) · Current Opinion in Physiology · doi:10.1016/j.cophys.2025.100849 · Cited by 2 · see citing works
Glioblastoma Multiforme miRNA based Comprehensive Study to Validate Phytochemicals for Effective Treatment against Deadly Tumour through In Silico Evaluation
Khan, R. B., Tiwari, S., Jarkharya, A., Tiwari, A., Chowdhary, R., & Shrivastava, A. (2024) · MicroRNA · doi:10.2174/0122115366302365240618122812 · Cited by 2 · see citing works
Anticancer effect of the antipsychotic agent penfluridol on epithelial ovarian cancer
Kim, W.-J., Ryu, J., Chang, C., Cho, Y.-J., Choi, J.-J., Hwang, J. R., Choi, J., & Lee, J. (2024) · Journal of Gynecologic Oncology · doi:10.3802/jgo.2025.36.e28 · Cited by 2 · see citing works
“Studies have reported that penfluridol induces the tumor suppressor PP2A in pancreatic cancer and leukemia cells, leading to AKT deactivation and resulting in apoptosis [20,34].”
Application of Connectivity Map Database to Research on Chinese Materia Medica
Lv, C., Wang, Y., Liu, R., & Zhang, W. (2016) · Chinese Herbal Medicines · doi:10.1016/s1674-6384(16)60019-9 · Cited by 2 · see citing works
A PP2A-mtATR-tBid axis links DNA damage-induced CIP2A degradation to apoptotic dormancy and therapeutic resistance in PDAC
Luo, Y., Biswas, H., Makinwa, Y., Liu, S., Dong, Z., Liu, J., Zhang, J., & Zou, Y. (2025) · Cancer Letters · doi:10.1016/j.canlet.2025.217790 · Cited by 1 · see citing works
THEEFFECT OF DOXORUBICIN AND THIORIDAZINE ON SQUAMOUS CARCINOMA CELL LINE
(2020) · Ain Shams Dental Journal · doi:10.21608/asdj.2020.164446 · Cited by 1 · see citing works
Causality between six psychiatric disorders and digestive tract cancers risk: a two-sample Mendelian randomization study
Fu, Q., Li, L.-H., Zhuoma, N., Ma, R., Zhao, Z.-X., Quzuo, Z., Wang, Z., Yangzong, D., & Di, J. (2024) · Scientific Reports · doi:10.1038/s41598-024-66535-7 · Cited by 1 · see citing works
“This multifaceted molecular modulation culminates in tumour cell death 63 .”
Background
SALIQ in Rhabdomyosarcoma: A Repurposed Multidrug Regimen to Augment Standard Treatments by Adding Simvastatin, All Trans Retinoic Acid, Lithium, Itraconazole, and QuercetinPreprint
Kast, R. E., Zaghloul, M. S., Sardi, I., & Halatsch, M. (2023) · Preprints.org · doi:10.20944/preprints202309.1957.v1 · Cited by 1 · see citing works
Application of Connectivity Map (CMAP) Database to Research on Traditional Chinese Medicines (TCMs)
Lv, C., Nagle, D. G., Zhou, Y., & Zhang, W. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-812744-5.00006-0
A pan-cancer analysis of the glutaminase and their association with prognosis, tumor microenvironment, and therapeutic targetsPreprint
Jin, S., & Kong, L. (2021) · Research Square · doi:10.21203/rs.3.rs-1078639/v1
Thioridazine enhances the effect of Doxorubicin on HEp-2 Cell Line
(2020) · Ain Shams Dental Journal · doi:10.21608/asdj.2020.140025
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Evaluation of Apoptotic and Autophagic Effects of Thioridazine in Monolayer and Spheroid Cell Cultures
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Antitumoral Effect on Liver Cancer of a Tumor-Penetrating and Interfering Peptide
Savier, É., Tufféry, P., Bruzoni-Giovannelli, H., Boudjelloul, R., & Rebollo, A. (2025) · Methods in pharmacology and toxicology · doi:10.1007/978-1-0716-4374-7_2
Impact of Tyrosine Kinase Inhibitors on the Expression Pattern of Epigenetic Regulators
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Additional file 7 of KLF14 regulates the growth of hepatocellular carcinoma cells via its modulation of iron homeostasis through the repression of iron-responsive element-binding protein 2
Zhou, H., Chen, J., Fan, M., Cai, H., Dong, Y., Qiu, Y., Zhuang, Q., Lei, Z., Li, M., Ding, X., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26559233
Additional file 4 of KLF14 regulates the growth of hepatocellular carcinoma cells via its modulation of iron homeostasis through the repression of iron-responsive element-binding protein 2
Zhou, H., Chen, J., Fan, M., Cai, H., Dong, Y., Qiu, Y., Zhuang, Q., Lei, Z., Li, M., Ding, X., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26559224
Additional file 9 of KLF14 regulates the growth of hepatocellular carcinoma cells via its modulation of iron homeostasis through the repression of iron-responsive element-binding protein 2
Zhou, H., Chen, J., Fan, M., Cai, H., Dong, Y., Qiu, Y., Zhuang, Q., Lei, Z., Li, M., Ding, X., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26559239
Additional file 1 of KLF14 regulates the growth of hepatocellular carcinoma cells via its modulation of iron homeostasis through the repression of iron-responsive element-binding protein 2
Zhou, H., Chen, J., Fan, M., Cai, H., Dong, Y., Qiu, Y., Zhuang, Q., Lei, Z., Li, M., Ding, X., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26559215
Additional file 6 of KLF14 regulates the growth of hepatocellular carcinoma cells via its modulation of iron homeostasis through the repression of iron-responsive element-binding protein 2
Zhou, H., Chen, J., Fan, M., Cai, H., Dong, Y., Qiu, Y., Zhuang, Q., Lei, Z., Li, M., Ding, X., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26559230
Additional file 8 of KLF14 regulates the growth of hepatocellular carcinoma cells via its modulation of iron homeostasis through the repression of iron-responsive element-binding protein 2
Zhou, H., Chen, J., Fan, M., Cai, H., Dong, Y., Qiu, Y., Zhuang, Q., Lei, Z., Li, M., Ding, X., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26559236
Additional file 3 of KLF14 regulates the growth of hepatocellular carcinoma cells via its modulation of iron homeostasis through the repression of iron-responsive element-binding protein 2
Zhou, H., Chen, J., Fan, M., Cai, H., Dong, Y., Qiu, Y., Zhuang, Q., Lei, Z., Li, M., Ding, X., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26559221
Additional file 5 of KLF14 regulates the growth of hepatocellular carcinoma cells via its modulation of iron homeostasis through the repression of iron-responsive element-binding protein 2
Zhou, H., Chen, J., Fan, M., Cai, H., Dong, Y., Qiu, Y., Zhuang, Q., Lei, Z., Li, M., Ding, X., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26559227
Additional file 2 of KLF14 regulates the growth of hepatocellular carcinoma cells via its modulation of iron homeostasis through the repression of iron-responsive element-binding protein 2
Zhou, H., Chen, J., Fan, M., Cai, H., Dong, Y., Qiu, Y., Zhuang, Q., Lei, Z., Li, M., Ding, X., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26559218
Additional file 1 of Human pancreatic cancer patients with Epithelial-to-Mesenchymal Transition and an aggressive phenotype show a disturbed balance in Protein Phosphatase Type 2A expression and functionality
van Pelt, J., Meeusen, B., Derua, R., Guffens, L., Cutsem, E. V., Janssens, V., & Verslype, C. (2024) · Figshare · doi:10.6084/m9.figshare.26588817
Développement d'antiviraux à large spectre contre le virus de la rage et les autres virus à ARN négatif
Kali, S. (2019) · doi:10.70675/6dee8050zaaffz41f0zbe6cz842eeba01121

Abstract 1291: Identification of penfluridol as potential treatment for pancreatic cancer cells.
Chien, W., Lee, K. L., Sun, Q., Wuensche, P., Sudo, M., Poellinger, L., Tyner, J. W., Yang, H. H., & Koeffler, H. P. (2013) · Cancer Research · doi:10.1158/1538-7445.am2013-1291 · Cited by 1 · see citing works
Abstract B21: Protein phosphatase 2A (PP2A) activation functions synergistically with kinase inhibition in pancreatic cancer
Allen-Petersen, B. L., Farrell, A. S., Jenny, Z. P., Daniel, C. J., Wang, Z., Lopez, C. D., Christensen, D. J., Narla, G., Sheppard, B. C., & Sears, R. C. (2015) · Molecular Cancer Research · doi:10.1158/1557-3125.myc15-b21
Abstract A104: Phosphatase activation and kinase inhibition as a novel therapeutic strategy for pancreatic cancer
Allen-Petersen, B. L., Farrell, A. S., Daniel, C. J., Wang, Z., Lopez, C. D., Christensen, D. J., Sheppard, B. C., & Sears, R. C. (2015) · Cancer Research · doi:10.1158/1538-7445.panca2014-a104
Targeting Inhibitors of the Tumor Suppressor PP2A for the Treatment of Pancreatic Cancer
Farrell, A. S., Allen-Petersen, B., Daniel, C. J., Wang, X., Wang, Z., Rodriguez, S., Impey, S., Oddo, J., Vitek, M. P., Lopez, C., et al. (2014) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-13-0542 · Cited by 114 · see citing works
Oncogenes and Tumor Suppressors Targeting Inhibitors of the Tumor Suppressor PP2A for the Treatment of Pancreatic Cancer
Farrell, A. S., Allen-petersen, B., Daniel, C. J., Wang, X., Wang, Z., Rodriguez, S., Impey, S., Vitek, M. P., Lopez, C., Christensen, D. J., et al. (2016)

Authors: Chien, W., Sun, Q.-Y., Lee, K. L., Ding, L.-W., Wuensche, P., Torres-Fernandez, L. A., Tan, S. Z., Tokatly, I., Zaiden, N., Poellinger, L., Mori, S., Yang, H., Tyner, J. W., & Koeffler, H. P.
Affiliations: National University of Singapore (SG)
Sheba Medical Center (IL)
Oregon Health & Science University (US)
Cedars-Sinai Medical Center (US)
Corresponding author: Chien, Wenwen
ORCID: Sun, Qiao-Yang
Lee, Kian Leong
Ding, Ling-Wen
Zaiden, Norazean
Mori, Seiichi
Yang, Henry
Tyner, Jeffrey W.
Koeffler, H. Phillip
Venue: Molecular Oncology
Publisher: Wiley
Published: 2015-01-15
Volume: 9
Issue: 4
Pages: 889-905
ISSN: 1574-7891 (ISSN-L)
1878-0261
DOI: 10.1016/j.molonc.2015.01.002
PMC: PMC4387089
OpenAlex: W2033599624
Cited by: 80
References: 58
Citations by year: 2025: 6 · 2024: 18 · 2023: 5 · 2022: 2 · 2021: 9 · 2020: 6 · 2019: 13 · 2018: 5 · 2017: 5 · 2016: 6 · 2015: 5
FWCI: 3.06
Type: journal article
Language: en
Update notices: expression_of_concern (2025-07-08)
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Molecular Oncology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
National University of Singapore (submittedVersion)
eScholarship (California Digital Library) (submittedVersion)
Funders: Singapore Ministry of Health's National Medical Research Council (NMRC) (NMRC/StaR/00007/2008)
National Research Foundation Singapore (NRF/RCE R-713-003-012-271)
Singapore Ministry of Education under its Research Centres of Excellence initiative (NRF/RCE R-713-003-012-271)
NIH (2R01CA026038-32)
Topics: Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords: pancreatic cancer, protein phosphatase 2A, PP2A activation, dasatinib, dasatinib resistance, thioridazine, phenothiazines, penfluridol, apoptosis, kinase inhibitors, drug repurposing, Connectivity Map, gene expression profiling, cell cycle regulation
MeSH terms: Dasatinib, Antineoplastic Agents, Cell Cycle, Computer Simulation, Drug Evaluation, Preclinical, Enzyme Activation, Humans, Pancreatic Neoplasms, Penfluridol, Phenothiazines, Gene Expression Regulation, Neoplastic, Apoptosis, Inhibitory Concentration 50, Tumor Suppressor Proteins, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, Protein Phosphatase 2

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Activation of protein phosphatase 2A tumor suppressor as potential treatment of pancreatic cancer

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