Prominin-1 glycosylation changes throughout early pregnancy in uterine epithelial cells under the influence of maternal ovarian hormones

Dowland, Samson N.; Madawala, Romanthi J.; Poon, Connie E.; Lindsay, Linda; Murphy, Christopher R.

doi:10.1071/rd15432

Cited by 8 publications

(9 citation statements)

References 60 publications

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“…One of the most commonly-used markers for stem cells for a number of cancers is CD133, known as prominin1 (PROM1), a pentaspan transmembrane glycoprotein also expressed in presumptive stem cells of some normal tissues. CD133 is believed to be a stem cell marker for normal hematopoietic cells [6,7], endothelial cells, neuronal and glial cells [6], as well as cells from adult kidney, mammary gland, trachea, salivary gland, uterus, placenta, digestive tract, testes, epidermal [8], and intestinal stem cells [9,10,11,12]. The importance of CD133 in retinal development has been shown in mouse knockout models, as well as in human genetic disorders in which mutations and deletions are associated with retinitis pigmentosa and macular degeneration [13,14,15].…”

Section: Introductionmentioning

confidence: 99%

CRISPR-Cas9 Knockdown and Induced Expression of CD133 Reveal Essential Roles in Melanoma Invasion and Metastasis

Simbulan-Rosenthal

Dougherty

Vakili

et al. 2019

Cancers

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CD133, known as prominin1, is a penta-span transmembrane glycoprotein presumably a cancer stem cell marker for carcinomas, glioblastomas, and melanomas. We showed that CD133(+) ‘melanoma-initiating cells’ are associated with chemoresistance, contributing to poor patient outcome. The current study investigates the role(s) of CD133 in invasion and metastasis. Magnetic-activated cell sorting of a melanoma cell line (BAKP) followed by transwell invasion assays revealed that CD133(+) cells are significantly more invasive than CD133(−) cells. Conditional reprogramming of BAKP CD133(+) cells maintained stable CD133 overexpression (BAK-R), and induced cancer stem cell markers, melanosphere formation, and chemoresistance to kinase inhibitors. BAK-R cells showed upregulated CD133 expression, and consequently were more invasive and metastatic than BAK-P cells in transwell and zebrafish assays. CD133 knockdown by siRNA or CRISPR-Cas9 (BAK-R-T3) in BAK-R cells reduced invasion and levels of matrix metalloproteinases MMP2/MMP9. BAK-R-SC cells, but not BAK-R-T3, were metastatic in zebrafish. While CD133 knockdown by siRNA or CRISPR-Cas9 in BAK-P cells attenuated invasion and diminished MMP2/MMP9 levels, doxycycline-induced CD133 expression in BAK-P cells enhanced invasion and MMP2/MMP9 concentrations. CD133 may therefore play an essential role in invasion and metastasis via upregulation of MMP2/MMP9, leading to tumor progression, and represents an attractive target for intervention in melanoma.

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Section: Introductionmentioning

confidence: 99%

CRISPR-Cas9 Knockdown and Induced Expression of CD133 Reveal Essential Roles in Melanoma Invasion and Metastasis

Simbulan-Rosenthal

Dougherty

Vakili

et al. 2019

Cancers

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“…Our study shows that prominin-2 is restricted to the basolateral plasma membrane during early pregnancy, in contrast to prominin-1, which is restricted to the apical domain of UECs. 35 At the time of fertilization during normal pregnancy, prominin-2 is present in the lateral and basal plasma membrane of UECs but is absent from the apical plasma membrane. This is a similar subcellular distribution to that previously observed in the distal convoluted tubule, connecting duct and collecting duct of the nephron.…”

Section: Discussionmentioning

confidence: 99%

“…[29][30][31] Prominin-1 is found in a range of cell types, 29,32 and recent studies have shown this protein is located in the apical region of UECs, both at the time of fertilization and at the time of implantation. [33][34][35] In contrast, prominin-2 appears to be restricted to epithelial cells including those in the esophagus, 36 kidney tubules, 37 urinary bladder, 38 and exocrine salivary glands. 39 Prominin-2 is also widely expressed throughout the male reproductive tract, including within epithelial cells lining the prostate gland, epididymis, and seminal vesicles.…”

Section: Introductionmentioning

confidence: 98%

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Prominin-2 Prevents the Formation of Caveolae in Normal and Ovarian Hyperstimulated Pregnancy

et al. 2017

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During early pregnancy, uterine epithelial cells (UECs) become less adherent to the underlying basal lamina and are subsequently removed so the blastocyst can invade the underlying stroma. This process involves the removal of focal adhesions from the basal plasma membrane of UECs. These focal adhesions are thought to be internalized by caveolae, which significantly increase in abundance at the time of blastocyst implantation. A recent in vitro study indicated that prominin-2 prevents the formation of caveolae by sequestering membrane cholesterol. The present study examines whether prominin-2 affects the formation of caveolae and loss of focal adhesions in UECs during normal and ovarian hyperstimulation (OH) pregnancy in the rat. At the time of fertilization during normal pregnancy, prominin-2 is distributed throughout the basolateral plasma membrane. However, at the time of implantation and coincident with an increase in caveolae, prominin-2 is lost from the basal plasma membrane. In contrast, prominin-2 remains in the basolateral plasma membrane throughout OH pregnancy. Transmission electron microscopy showed that this membrane contained few caveolae throughout OH pregnancy. Our results indicate that prominin-2 prevents the formation of caveolae. We suggest the retention of prominin-2 in the basal plasma membrane during OH pregnancy prevents the formation of caveolae and is responsible for the retention of focal adhesions in this membrane, thereby contributing to the reduced implantation rate observed after such treatments.

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“…The 97 kDa transmembrane glycoprotein CD133, also known as prominin1 (PROM1), is expressed in stem cells of normal neuronal and glial cells, hematopoietic cells, endothelial cells, and cells from adult kidney, mammary gland, salivary gland, placenta, trachea, testes, uterus, epidermis, and intestine [23][24][25][26][27][28]. CD133 is also expressed in cancer stem cells from multiple organs, including cancers of the brain, ovary, liver, prostate, pancreas, colon, in addition to melanomas [29][30][31][32][33][34][35][36][37].…”

Section: Introductionmentioning

confidence: 99%

CD133 Promotes Resistance to Trametinib in Melanoma Stem Cells by Activating an AKT / BCL-2 Survival Pathway

Cm¹,

Haribabu²,

Vakili³

et al. 2021

Preprint

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Malignant melanoma is a lethal skin cancer containing melanoma-initiating cells (MIC), implicated in tumorigenesis, invasion, and drug resistance, and characterized by elevated expression of stem cell markers, such as CD133. We previously showed that siRNA knockdown of CD133 enhances apoptosis induced by the MEK inhibitor trametinib in melanoma cells. The current study investigates underlying mechanisms of CD133’s anti-apoptotic activity in patient-derived BAKP and POT cells, harboring difficult-to-treat NRASQ61K and NRASQ61R drivers, after CRISPR-Cas9 CD133 knockdown or Dox-inducible expression of CD133. To maintain stable expression of CD133, MACS-sorted CD133(+) positive cells were expanded by ROCK-mediated conditional reprogramming of BAKP melanoma cells (BAKR). BAKR showed increased survival via reduced apoptosis after exposure to trametinib or DTIC, compared to BAKP. CRISPR-Cas9- mediated CD133 knockdown in BAKR cells (BAKR-T3) re-sensitized the cells, while CRISPR-Cas9 knockdown of CD133 in parental BAKP and POT cells even further increased trametinib-induced apoptosis (cleaved PARP) by reducing levels of anti-apoptotic BCL-xL, p-AKT, and p-BAD, and increasing pro-apoptotic BAD and active BAX. Dox-induced CD133 overexpression had the opposite effect, and blocked trametinib-induced apoptosis in both cell lines, coincident with elevated p-AKT, p-BAD, BCL-2 and BCL-xL and decreased levels of the active form of BAX and caspases-3 and -9. The roles of CD133 in AKT and BAD phosphorylation, or in the upregulation of anti-apoptotic BCL-2 family members, was further investigated by AKT knockout with siRNA, or inhibition of BCL-2 family members with navitoclax (ABT-263). Similar to CD133 knockdown, AKT1/2 siRNA knockdown in BAKP cells also reduced p-BAD. CD133 knockdown (T3)-mediated reduction of pBAD levels was equivalent in AKT-knockdown or AKT control cells indicating that CD133 may be upstream of AKT signaling. In BAKP cells treated with trametinib and/or ABT-263, effects of ABT-263 mirrored CD133 knockdown, since levels of active BAX and cleaved-PARP in BAKP-SC (CD133-) cells increased to the same level as that exhibited by BAKP-T3 cells (CD133+). CD133 may therefore activate a survival pathway where 1) increased phosphorylation of AKT induces 2) phosphorylation and inactivation of BAD, 3) decrease in the active form of BAX, and 4) reduction in caspase-mediated PARP cleavage, indicating apoptosis suppression leading to drug resistance in melanomas. Targeting survival pathways by which CD133 may confer chemoresistance in MICs can contribute to development of more effective treatments for patients with high-risk melanoma.

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Prominin-1 glycosylation changes throughout early pregnancy in uterine epithelial cells under the influence of maternal ovarian hormones

Cited by 8 publications

References 60 publications

CRISPR-Cas9 Knockdown and Induced Expression of CD133 Reveal Essential Roles in Melanoma Invasion and Metastasis

CRISPR-Cas9 Knockdown and Induced Expression of CD133 Reveal Essential Roles in Melanoma Invasion and Metastasis

Prominin-2 Prevents the Formation of Caveolae in Normal and Ovarian Hyperstimulated Pregnancy

CD133 Promotes Resistance to Trametinib in Melanoma Stem Cells by Activating an AKT / BCL-2 Survival Pathway

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