Trifluoperazine, a Well-Known Antipsychotic, Inhibits Glioblastoma Invasion by Binding to Calmodulin and Disinhibiting Calcium Release Channel IP3R

Kang, Seok-Min; Hong, Jinpyo; Lee, Jung Moo; Moon, Hyo Eun; Jeon, Borami; Choi, Jungil; Yoon, Nal Ae; Paek, Sun Ha; Roh, Eun Joo; Lee, C. Justin; Kang, Sang Soo

doi:10.1158/1535-7163.mct-16-0169-t

Cited by 86 publications

(69 citation statements)

References 35 publications

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“…In the above study, the SF 2Gy (surviving fraction at 2 Gy) values for glioma cells in vitro were comparable to those of other cancers including squamous cell carcinoma, colon cancer, and soft tissue sarcoma (6). Likewise, TCD 50 (the radiation dose necessary to control 50% of the tumors locally) values were not exceptionally high and TCD 50 and SF 2Gy values did not correlate with each other (6). With most systemic agents being ineffective and surgery and RT having reached their maximum potential, treatment for GBM has hit a critical barrier.…”

Section: Introductionsupporting

confidence: 68%

“…Short-term 21-day monotherapy with lower doses (10 mg/kg) of TFP against U87MG xenografts has been previously reported but did not yield a survival benefit (50). A second study reported radiosensitization of U87MG and U251 cells based on increased gamma-H2AX foci formation and inhibition of DNA repair by homologous recombination.…”

Section: The Phenotype Conversion Of Non-tumorigenic Cells Into Radiomentioning

confidence: 89%

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The Dopamine Receptor Antagonist TFP Prevents Phenotype Conversion and Improves Survival in Mouse Models of Glioblastoma

Bhat¹,

Saki²,

Vlashi³

et al. 2019

Preprint

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Glioblastoma (GBM) is the deadliest adult brain cancer and all patients ultimately succumb to the disease. Radiation therapy (RT) provides survival benefit of 6 months over surgery alone but these results have not improved in decades. We report that radiation induces a glioma-initiating cell phenotype and we have identified trifluoperazine (TFP) as a compound that interferes with this phenotype conversion. TFP caused loss of radiation-induced Nanog mRNA expression, activation of GSK3 with consecutive post-translational reduction in p-Akt, Sox2and -catenin protein levels. TFP did not alter the intrinsic radiation sensitivity of glioma-initiating cells (GICs). Continuous treatment with TFP and a single dose of radiation reduced the number of GICs in vivo and prolonged survival in syngeneic and patient-derived orthotopic xenograft (PDOX) mouse models of GBM. Our findings suggest that combination of a dopamine receptor antagonist with radiation enhances the efficacy of RT in GBM by preventing radiationinduced phenotype conversion of radiosensitive non-GICs into treatment resistant, induced GICs. SignificanceGBM is the most common and most deadly adult brain cancer. The current standard-of-care is surgery followed by RT and temozolomide, which results in a median survival time of only 15 months. The efficacy of chemotherapies and targeted therapies in GBM is very limited because most of these drugs do not pass the blood-brain-barrier. Ultimately, all patients succumb to the disease.Our study describes radiation-induced cellular plasticity as a novel resistance mechanism in GBM. We identified a dopamine receptor antagonist as a readily available, FDA-approved drug known to penetrate the blood-brain-barrier which prevents phenotype conversion of glioma cells into glioma-initiating cells and prologs survival in mouse models of GBM, thus suggesting that it will improve the efficacy of RT without increasing toxicity.

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Section: Introductionsupporting

confidence: 68%

Section: The Phenotype Conversion Of Non-tumorigenic Cells Into Radiomentioning

confidence: 89%

The Dopamine Receptor Antagonist TFP Prevents Phenotype Conversion and Improves Survival in Mouse Models of Glioblastoma

Bhat¹,

Saki²,

Vlashi³

et al. 2019

Preprint

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“…In glioblastoma, TFP suppresses tumor cell proliferation and invasion in vitro and in vivo . Thereby, TFP binds to CaM and causes its dissociation from inositol 1,4,5‐triphosphate receptor leading to channel opening and increase in intracellular calcium levels (Kang et al , ). The anti‐estrogen TMX antagonistically binds to the estrogen receptor (ER) and to CaM in a calcium‐dependent manner (Lopes et al , ).…”

Section: Discussionmentioning

confidence: 99%

The brain acid‐soluble protein 1 (BASP1) interferes with the oncogenic capacity of MYC and its binding to calmodulin

et al. 2020

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The MYC protein is a transcription factor with oncogenic potential controlling fundamental cellular processes such as cell proliferation, metabolism, differentiation, and apoptosis. The MYC gene is a major cancer driver, and elevated MYC protein levels are a hallmark of most human cancers. We have previously shown that the brain acid‐soluble protein 1 gene (BASP1) is specifically downregulated by the v‐myc oncogene and that ectopic BASP1 expression inhibits v‐myc‐induced cell transformation. The 11‐amino acid effector domain of the BASP1 protein interacts with the calcium sensor calmodulin (CaM) and is mainly responsible for this inhibitory function. We also reported recently that CaM interacts with all MYC variant proteins and that ectopic CaM increases the transactivation and transformation potential of the v‐Myc protein. Here, we show that the presence of excess BASP1 or of a synthetic BASP1 effector domain peptide leads to displacement of v‐Myc from CaM. The protein stability of v‐Myc is decreased in cells co‐expressing v‐Myc and BASP1, which may account for the inhibition of v‐Myc. Furthermore, suppression of v‐Myc‐triggered transcriptional activation and cell transformation is compensated by ectopic CaM, suggesting that BASP1‐mediated withdrawal of CaM from v‐Myc is a crucial event in the inhibition. In view of the tumor‐suppressive role of BASP1 which was recently also reported for human cancer, small compounds or peptides based on the BASP1 effector domain could be used in drug development strategies aimed at tumors with high MYC expression.

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“…Moreover, the selective inhibition of IP 3 Rs and SOCE lead to reduced cell migration underlying the importance of Ca 2+ signaling in this process (127). Increased IP 3 R3 expression and IP 3 R-derived Ca 2+ signals have also been shown to correlate with the invasive properties of glioblastoma cells (128, 129). Inhibition of IP 3 Rs with caffeine inhibited the invasion and migration of glioblastoma cells and increased the survival of mice xenografted with glioblastoma cells (128).…”

Section: Ip3rs and Autophagy In Cancermentioning

confidence: 99%

“…TFP-induced Ca 2+ rise also depended on the presence of the calmodulin subtype 2 (CaM2) protein, which correlates with previous work revealing TFP as a calmodulin-inhibitory molecule by inducing a conformational change in Ca 2+ -calmodulin (130). Hence, it was proposed that TFP by targeting and antagonizing CaM2 alleviates CaM2’s inhibitory action on IP 3 Rs, resulting in a potent and irreversible Ca 2+ release, responsible for the cell growth and invasion restraint of glioblastoma cells (129). More recently, IP 3 R-mediated Ca 2+ signaling has been shown to be critical for normal T-cell development through repression of Sox1, an antagonist of the transcription factor Tcf1, which is important for normal T-cell development.…”

Section: Ip3rs and Autophagy In Cancermentioning

confidence: 99%

IP3 Receptor-Mediated Calcium Signaling and Its Role in Autophagy in Cancer

et al. 2017

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Calcium ions (Ca2+) play a complex role in orchestrating diverse cellular processes, including cell death and survival. To trigger signaling cascades, intracellular Ca2+ is shuffled between the cytoplasm and the major Ca2+ stores, the endoplasmic reticulum (ER), the mitochondria, and the lysosomes. A key role in the control of Ca2+ signals is attributed to the inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), the main Ca2+-release channels in the ER. IP3Rs can transfer Ca2+ to the mitochondria, thereby not only stimulating core metabolic pathways but also increasing apoptosis sensitivity and inhibiting basal autophagy. On the other hand, IP3-induced Ca2+ release enhances autophagy flux by providing cytosolic Ca2+ required to execute autophagy upon various cellular stresses, including nutrient starvation, chemical mechanistic target of rapamycin inhibition, or drug treatment. Similarly, IP3Rs are able to amplify Ca2+ signals from the lysosomes and, therefore, impact autophagic flux in response to lysosomal channels activation. Furthermore, indirect modulation of Ca2+ release through IP3Rs may also be achieved by controlling the sarco/endoplasmic reticulum Ca2+ ATPases Ca2+ pumps of the ER. Considering the complex role of autophagy in cancer development and progression as well as in response to anticancer therapies, it becomes clear that it is important to fully understand the role of the IP3R and its cellular context in this disease. In cancer cells addicted to ER–mitochondrial Ca2+ fueling, IP3R inhibition leads to cancer cell death via mechanisms involving enhanced autophagy or mitotic catastrophe. Moreover, IP3Rs are the targets of several oncogenes and tumor suppressors and the functional loss of these genes, as occurring in many cancer types, can result in modified Ca2+ transport to the mitochondria and in modulation of the level of autophagic flux. Similarly, IP3R-mediated upregulation of autophagy can protect some cancer cells against natural killer cells-induced killing. The involvement of IP3Rs in the regulation of both autophagy and apoptosis, therefore, directly impact cancer cell biology and contribute to the molecular basis of tumor pathology.

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Trifluoperazine, a Well-Known Antipsychotic, Inhibits Glioblastoma Invasion by Binding to Calmodulin and Disinhibiting Calcium Release Channel IP3R

Cited by 86 publications

References 35 publications

The Dopamine Receptor Antagonist TFP Prevents Phenotype Conversion and Improves Survival in Mouse Models of Glioblastoma

The Dopamine Receptor Antagonist TFP Prevents Phenotype Conversion and Improves Survival in Mouse Models of Glioblastoma

The brain acid‐soluble protein 1 (BASP1) interferes with the oncogenic capacity of MYC and its binding to calmodulin

IP3 Receptor-Mediated Calcium Signaling and Its Role in Autophagy in Cancer

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