CDC50A plays a key role in the uptake of the anticancer drug perifosine in human carcinoma cells

Muñoz-Martínez, Francisco; Torres, Cristina; Castanys, Santiago; Gamarro, Francisco

doi:10.1016/j.bcp.2010.05.017

Cited by 23 publications

(14 citation statements)

References 31 publications

(53 reference statements)

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“…TMEM30A -deficient cells are engulfed by macrophages because of the exposure of PS in the exoplasmic leaflet, and these cells lost the ability to induce tumor formation in nude mice 13 . TMEM30A also promotes uptake of the anticancer drugs and choline phospholipids into mammalian cells 38,39 . Most recently, a number of studies have highlighted the importance of TMEM30A in vivo.…”

Section: Introductionmentioning

confidence: 99%

Disruption of Tmem30a results in cerebellar ataxia and degeneration of Purkinje cells

et al. 2018

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Phospholipids are asymmetrically distributed across mammalian plasma membrane with phosphatidylserine (PS) and phosphatidylethanolamine concentrated in the cytoplasmic leaflet of the membrane bilayer. This asymmetric distribution is dependent on a group of P4-ATPases named PS flippases. The proper transport and function of PS flippases require a β-subunit transmembrane protein 30 A (TMEM30A). Disruption of PS flippases led to several human diseases. However, the roles of TMEM30A in the central nervous system remain elusive. To investigate the role of Tmem30a in the cerebellum, we developed a Tmem30a Purkinje cell (PC)-specific knockout (KO) mouse model. The Tmem30a KO mice displayed early-onset ataxia and progressive PC death. Deficiency in Tmem30a led to an increased expression of Glial fibrillary acidic protein and astrogliosis in regions with PC loss. Elevated C/EBP homologous protein and BiP expression levels indicated the presence of endoplasmic reticulum stress in the PCs prior to visible cell loss. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis suggested that apoptotic cell death occurred in the cerebellum. Our data demonstrate that loss of Tmem30a in PCs results in protein folding and transport defects, a substantial decrease in dendritic spine density, increased astrogliosis and PC death. Taken together, our data demonstrate an essential role of Tmem30a in the cerebellum PCs.

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Section: Introductionmentioning

confidence: 99%

Disruption of Tmem30a results in cerebellar ataxia and degeneration of Purkinje cells

et al. 2018

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“…TMEM30A also contributes to the uptake of anticancer drugs and choline phospholipids into mammalian cells(Muñozmartínez et al . ; Chen et al . ).…”

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confidence: 99%

Tmem30a deficiency leads to retinal rod bipolar cell degeneration

Yang

Liu

Sun

et al. 2019

Journal of Neurochemistry

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Phospholipids are asymmetrically distributed across the mammalian plasma membrane, with phosphatidylserine (PS) and phosphatidylethanolamine concentrated in the cytoplasmic leaflet of the membrane bilayer and phosphatidylcholine in the exoplasmic leaflet. This asymmetric distribution is dependent on a group of P4 ATPases called PS flippases. The proper transport and function of PS flippases require a β‐subunit transmembrane protein 30A (TMEM30A). Disruption of PS flippases leads to several human diseases. Tmem30a is essential for photoreceptor survival. However, the roles of Tmem30a in the retinal rod bipolar cells (RBC) remain elusive. To investigate the role of Tmem30a in the RBCs, we generated a RBC‐specific Tmem30a knockout (cKO) mouse model using PCP2‐Cre line. The Tmem30a cKO mice exhibited defect in RBC function and progressive RBC death. PKCα staining of retinal cryosections from cKO mice revealed a remarkable dendritic sprouting of rod bipolar cells during the early degenerative process. Immunostaining analysis of PSD95 and mGluT6 expression demonstrated that rod bipolar cells in Tmem30a cKO retinas exhibited aberrant dendritic sprouting as a result of impaired synaptic efficacy, which implied a crucial role for Tmem30a in synaptic transmission in the retina. In addition, loss of Tmem30a led to reactive gliosis with increased expression of glial fibrillary acidic protein and CD68. TUNEL staining suggested that apoptotic cell death occurred in the retinal inner nuclear layer (INL). Our data show that loss of Tmem30a in RBCs results in dendritic sprouting of rod bipolar cells, increased astrogliosis and RBC death. Taken together, our studies demonstrate an essential role for Tmem30a in the retinal bipolar cells. Cover Image for this issue: doi: .

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“…The PCR was performed as following: initial denaturation at 95 °C for 5 min, 40 cycles for amplification at 95 °C for 30 s, 62 °C for 30 s and 72 °C for 30 s, final elongation at 72 °C for 5 min. Primer sequences were taken as described for ATP8B1 47 , CDC50A and β -Actin 48 . For the MGMT assay cells were treated with pre-warmed medium containing 10 µM O 6 BG-Glu for 15 min at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

Uptake of glucose-conjugated MGMT inhibitors in cancer cells: role of flippases and type IV P-type ATPases

Tomaszowski

Hellmann

Ponath

et al. 2017

Sci Rep

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The DNA repair protein O 6-methylguanine-DNA-methyltransferase (MGMT) is a key determinant of cancer resistance. The MGMT inhibitors O 6-benzylguanine (O6BG) and O 6-(4-bromothenyl)guanine (O6BTG) failed to enhance the therapeutic response due to toxic side effects when applied in combination with alkylating chemotherapeutics, indicating a need of inhibitor targeting. We assessed MGMT targeting that relies on conjugating the inhibitors O6BG and O6BTG to ß-D-glucose, resulting in O6BG-Glu and O6BTG-Glu, respectively. This targeting strategy was selected by taking advantage of high demand of glucose in cancers. Contrary to our expectation, the uptake of O6BG-Glu and O6BTG-Glu was not dependent on glucose transporters. Instead, it seems that after membrane binding the conjugates are taken up via flippases, which normally transport phospholipids. This membrane binding is the consequence of the amphiphilic character of the conjugates, which at higher concentrations lead to the formation of micelle-like particles in aqueous solution. The unusual uptake mechanism of the conjugates highlights the importance of proper linker selection for a successful ligand-based drug delivery strategy. We also demonstrate that proteins of the P4-Type ATPase family are involved in the transport of the glucose conjugates. The findings are not only important for MGMT inhibitor targeting, but also for other amphiphilic drugs.

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CDC50A plays a key role in the uptake of the anticancer drug perifosine in human carcinoma cells

Cited by 23 publications

References 31 publications

Disruption of Tmem30a results in cerebellar ataxia and degeneration of Purkinje cells

Disruption of Tmem30a results in cerebellar ataxia and degeneration of Purkinje cells

Tmem30a deficiency leads to retinal rod bipolar cell degeneration

Uptake of glucose-conjugated MGMT inhibitors in cancer cells: role of flippases and type IV P-type ATPases

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