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

Chien, Wenwen; Sun, Qi‐Yun; 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 56 publications

(62 citation statements)

References 53 publications

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“…Our results showed an IC 50 ranging between 5–8µM and 3–5µM after 24h and 48h treatment respectively in all the breast cancer cell lines tested. In another recent study, PF was shown to induce apoptosis in pancreatic cancer cells by activating protein phosphatase 2A (PP2A) (41). Our results also showed suppression of cell migration and invasion by PF treatment, suggesting anti-metastatic effects in TNBC cells.…”

Section: Discussionmentioning

confidence: 99%

Penfluridol: An Antipsychotic Agent Suppresses Metastatic Tumor Growth in Triple-Negative Breast Cancer by Inhibiting Integrin Signaling Axis

2016

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Metastasis of breast cancer, especially to the brain, is the major cause of mortality. The inability of anti-cancer agents to cross the blood-brain-barrier represents a critical challenge for successful treatment. In the current study, we investigated the anti-metastatic potential of penfluridol (PF), an antipsychotic drug frequently prescribed for schizophrenia with anti-cancer activity. We show that PF induced apoptosis and reduced the survival of several metastatic triple negative breast cancer (TNBC) cell lines. Additionally, PF treatment significantly reduced the expression of integrinα6, integrin β4, Fak, Paxillin, Rac1/2/3, and ROCK1 in vitro. We further evaluated the efficacy of PF in three different in vivo tumor models. We demonstrate that PF administration to an orthotopic model of breast cancer suppressed tumor growth by 49%. On the other hand, PF treatment inhibited the growth of metastatic brain tumors introduced by intracardiac or intracranial injection of breast cancer cells by 90% and 72%, respectively. PF-treated tumors from all three models exhibited reduced integrinβ4 and increased apoptosis. Moreover, chronic administration of PF failed to elicit significant toxic or behavioral side effects in mice. Taken together, our result indicate that PF effectively reduces the growth of primary TNBC tumors and especially metastatic growth in the brain by inhibiting integrin signaling, and prompt further preclinical investigation into repurposing PF for the treatment of metastatic TNBC.

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Section: Discussionmentioning

confidence: 99%

Penfluridol: An Antipsychotic Agent Suppresses Metastatic Tumor Growth in Triple-Negative Breast Cancer by Inhibiting Integrin Signaling Axis

2016

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“…22 Penfluridol has been shown to activate protein phosphatase 2A and inhibit pancreatic cancer. 10 Recently, we have demonstrated that penfluridol, an antipsychotic drug, induced autophagy-mediated apoptosis and pancreatic tumor growth suppression. 11 However, the mechanism behind penfluridol-induced autophagy in pancreatic cancer is unknown.…”

Section: Discussionmentioning

confidence: 99%

Penfluridol induces endoplasmic reticulum stress leading to autophagy in pancreatic cancer

et al. 2017

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Pancreatic cancer is one of the most aggressive and difficult to treat cancers. Experimental and clinical evidence suggests that high basal state autophagy in pancreatic tumors could induce resistance to chemotherapy. Recently, we have demonstrated that penfluridol suppresses pancreatic tumor growth by autophagy-mediated apoptosis both in vitro and in vivo; however, the mechanism of autophagy induction by penfluridol was not clear. Several studies have established that endoplasmic reticulum stress could lead to autophagy and inhibit tumor progression. In this study, we demonstrated that penfluridol induced endoplasmic reticulum stress in BxPC-3, AsPC-1, and Panc-1 pancreatic cancer cell lines as indicated by upregulation of endoplasmic reticulum stress markers such as binding protein (BIP), C/EBP homologous protein (CHOP) and inositol requiring 1α (IRE1α) after treatment with penfluridol in a concentration-dependent manner. Inhibiting endoplasmic reticulum stress by pretreatment with pharmacological inhibitors such as sodium phenylbutyrate and mithramycin or by silencing CHOP using CHOP small interfering RNA, blocked penfluridol-induced autophagy. These results clearly indicate that penfluridol-induced endoplasmic reticulum stress lead to autophagy in our model. Western blot analysis of subcutaneously implanted AsPC-1 and BxPC-3 tumors as well as orthotopically implanted Panc-1 tumors demonstrated upregulation of BIP, CHOP, and IRE1α expression in the tumor lysates from penfluridol-treated mice as compared to tumors from control mice. Altogether, our study establishes that penfluridol-induced endoplasmic reticulum stress leads to autophagy resulting in reduced pancreatic tumor growth. Our study opens a new therapeutic target for advanced chemotherapies against pancreatic cancer.

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“…This approach has been particularly successful with non-steroidal antiinflammatory drugs (NSAIDs) and antidiabetics such as metformin (1,2). Phenothiazine-derived antipsychotic drugs such as thioridazine and chlorpromazine exhibit anticarcinogenic activity in several different cancer cell lines (3–9). More recent studies have demonstrated that penfluridol, another antipsychotic drug, also inhibits breast and pancreatic cancer cell growth (9,10).…”

Section: Introductionmentioning

confidence: 99%

“…Phenothiazine-derived antipsychotic drugs such as thioridazine and chlorpromazine exhibit anticarcinogenic activity in several different cancer cell lines (3–9). More recent studies have demonstrated that penfluridol, another antipsychotic drug, also inhibits breast and pancreatic cancer cell growth (9,10). For example, in pancreatic cancer a series of phenothiazene analogs induced apoptosis and inhibited clonogenic growth and colony formation, and more detailed studies with penfluridol indicated that induction of protein phosphatase 2A (PP2A) was a key effect of this compound (9).…”

Section: Introductionmentioning

confidence: 99%

“…More recent studies have demonstrated that penfluridol, another antipsychotic drug, also inhibits breast and pancreatic cancer cell growth (9,10). For example, in pancreatic cancer a series of phenothiazene analogs induced apoptosis and inhibited clonogenic growth and colony formation, and more detailed studies with penfluridol indicated that induction of protein phosphatase 2A (PP2A) was a key effect of this compound (9). Penfluridol exhibited antimetastatic activity in triple negative breast cancer cells and inhibited tumor growth and brain metastasis in three different in vivo models and the key elements were inhibition of α6- and β4-integrin expression (10).…”

Section: Introductionmentioning

confidence: 99%

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Penfluridol Represses Integrin Expression in Breast Cancer through Induction of Reactive Oxygen Species and Downregulation of Sp Transcription Factors

Hedrick

Safe

2017

Molecular Cancer Therapeutics

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It was recently demonstrated the penfluridol inhibited breast tumor growth and metastasis and this was associated with downregulation of α6- and β4-integrins. In this study, we observed the penfluridol induced reactive oxygen species (ROS) and this was the primary mechanism of action. Penfluridol-mediated growth inhibition, induction of apoptosis, and inhibition breast cancer cell migration was attenuated after cotreatment with glutathione (GSH). Penfluridol also downregulated Sp transcription factors Sp1, Sp3 and Sp4 through epigenetic downregulation of cMyc and cMyc-regulated microRNAs (miR-27a and miR-20a/miR-17) and induction of the miR-regulated Sp transcriptional repressors ZBTB10 and ZBTB4. α6- and β4-Integrins as well as α5- and β1-integrin are Sp-regulated genes that are also coregulated by the orphan nuclear receptor NR4A1 and these integrins can be targeted by agents such as penfluridol that suppress Sp1, Sp3 and Sp4 and also by NR4A1 antagonists.

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

Cited by 56 publications

References 53 publications

Penfluridol: An Antipsychotic Agent Suppresses Metastatic Tumor Growth in Triple-Negative Breast Cancer by Inhibiting Integrin Signaling Axis

Penfluridol: An Antipsychotic Agent Suppresses Metastatic Tumor Growth in Triple-Negative Breast Cancer by Inhibiting Integrin Signaling Axis

Penfluridol induces endoplasmic reticulum stress leading to autophagy in pancreatic cancer

Penfluridol Represses Integrin Expression in Breast Cancer through Induction of Reactive Oxygen Species and Downregulation of Sp Transcription Factors

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