Neuropilin-2 axis in regulating secretory phenotype of neuroendocrine-like prostate cancer cells and its implication in therapy resistance

Islam, Ridwan; Mishra, Juhi; Polavaram, Navatha S.; Bhattacharya, Sreyashi; Zhou, Hong; Bodas, Sanika; Sharma, Sunandini; Bouska, Alyssa; Gilbreath, Tyler; Said, Ahmed A.; Smith, Lynette M.; Teply, Benjamin A.; Muders, Michael H.; Batra, Surinder K.; Datta, Kaustubh; Dutta, Samikshan

doi:10.1016/j.celrep.2022.111097

Cited by 9 publications

(26 citation statements)

References 68 publications

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“…1E ). A similar marked induction of GD2 expression was seen when GD2-low LNCaP-C4-2B CRPC cells were compared to their enzalutamide-resistant derivative LNCaP C4-2BER (28) ( Table 1, Supplementary Fig. S2 ).…”

Section: Discussionsupporting

confidence: 56%

“…Depletion of RB1 or TP53 in CRPC-AR cell lines (34) and in mouse models, including when combined with PTEN loss (35), is known to promote the NE trans-differentiation. Therefore, we compared the functional AR-expressing CRPC cell line LNCaP C4-2, which has a mutational inactivation of PTEN (36), with its derivatives with stable knockdown (KD) of TP53 or RB1 (28), with verification of the KD using q-PCR (Fig. 1B).…”

Section: Resultsmentioning

confidence: 99%

“…HEK-293T cells (ATCC CRL-3216) were cultured in complete DMEM medium. LNCaP C4-2 parental, p53 stable KD, Rb1 KD cell lines, as well as the parental LNCaP C4-2B and its enzalutamide resistant derivative line (C4-2BER) were grown as described previously (28). Cell lines were maintained for less than 30 days in continuous culture and were regularly tested for mycoplasma.…”

Section: Methodsmentioning

confidence: 99%

“…The copyright holder for this preprint this version posted March 22, 2023. ; https://doi.org/10.1101/2023.03. 18.533299 doi: bioRxiv preprint high proportion of GD2 + cells with high mean fluorescence intensities (MFI's) was observed in the human CRPC cell lines 22Rv1, which overexpresses wildtype AR and ARV7 splice variant (37), and LNCaP C4-2B cells rendered enzalutamide-resistant (28), and on the murine CRPC cell line RM-1 (driven by Ras and Myc) (38) and TRAMP-transgenic mouse-derived TRAMP-C1 cell line (39) (Table 1, Supplementary Fig. 2A-C).…”

Section: Increased Gd2 Expression Across Pc Cell Lines Including Crpc...mentioning

confidence: 99%

“…The copyright holder for this preprint this version posted March 22, 2023. ; https://doi.org/10.1101/2023.03.18.533299 doi: bioRxiv preprint CRPC cells were compared to their enzalutamide-resistant derivative LNCaP C4-2BER (28) (Table 1, Supplementary Fig. S2).…”

Section: E) a Similar Marked Induction Of Gd2 Expression Was Seen Whe...mentioning

confidence: 99%

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GD2 and its biosynthetic enzyme GD3 synthase promote tumorigenesis in prostate cancer by regulating cancer stem cell behavior

Bhat

Mohapatra

Luan

et al. 2023

Preprint

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While better management of loco-regional prostate cancer (PC) has greatly improved survival, advanced PC remains a major cause of cancer deaths. Novel, targetable, pathways that contribute to tumorigenesis in advanced PC could open new therapeutic options. The di-ganglioside GD2 is a target of FDA-approved antibody therapies in neuroblastoma, but any role of GD2 in PC is little explored. Here, we show that GD2 is expressed on a small subpopulation of tumor cells in a subset of PC patients, especially in metastatic PC. Variable levels of cell surface GD2 expression are seen in most PC cell lines, and the expression is highly upregulated by experimental induction of lineage progression or enzalutamide resistance in CRPC cell models. GD2+ fraction is enriched upon growth of PC cells as tumorspheres and GD2+ fraction is enriched in tumorsphere growth. CRISPR-Cas9 knockout (KO) of the rate-limiting GD2 biosynthetic enzyme GD3 Synthase (GD3S) in GD2-high CRPC cell models led to marked impairment of their in vitro oncogenic traits, reduced cancer stem cell and epithelial-mesenchymal transition marker expression and growth as bone-implanted xenograft tumors. Our results support a potential role of GD3S and its product GD2 in promoting PC tumorigenesis, likely by its recently demonstrated role in maintaining cancer stem cells and suggest the potential for GD2 targeting in advanced PC.

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Section: Discussionsupporting

confidence: 56%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Increased Gd2 Expression Across Pc Cell Lines Including Crpc...mentioning

confidence: 99%

Section: E) a Similar Marked Induction Of Gd2 Expression Was Seen Whe...mentioning

confidence: 99%

See 3 more Smart Citations

GD2 and its biosynthetic enzyme GD3 synthase promote tumorigenesis in prostate cancer by regulating cancer stem cell behavior

Bhat

Mohapatra

Luan

et al. 2023

Preprint

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Identification of PRDX5 as A Target for The Treatment of Castration‐Resistant Prostate Cancer

Wang,

Mi,

et al. 2023

Advanced Science

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Treatment of castration‐resistant prostate cancer (CRPC) is a long‐standing clinical challenge. Traditionally, CRPC drugs work by either reducing dihydrotestosterone biosynthesis or blocking androgen receptor (AR) signaling. Here it is demonstrated that AR inhibitor treatment gives rise to a drug‐tolerant persister (DTP) state. The thioredoxin/peroxiredoxin pathway is up‐regulated in DTP cells. Peroxiredoxin 5 (PRDX5) promotes AR inhibitor resistance and CRPC development. Inhibition of PRDX5 suppresses DTP cell proliferation in culture, dampens CRPC development in animal models, and stabilizes PSA progression and metastatic lesions in patients. Therefore, the study provides a novel mechanism and potential target for the management of castration‐resistant prostate cancer.

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Role of Neuropilin-2-mediated signaling axis in cancer progression and therapy resistance

Islam

Mishra

Bodas

et al. 2022

Cancer Metastasis Rev

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Neuropilins (NRPs) are transmembrane proteins involved in vascular and nervous system development by regulating angiogenesis and axon guidance cues. Several published reports have established their role in tumorigenesis. NRPs are detectable in tumor cells of several cancer types and participate in cancer progression. NRP2 is also expressed in endothelial and immune cells in the tumor microenvironment and promotes functions such as lymphangiogenesis and immune suppression important for cancer progression. In this review, we have taken a comprehensive approach to discussing various aspects of NRP2-signaling in cancer, including its regulation, functional significance in cancer progression, and how we could utilize our current knowledge to advance the studies and target NRP2 to develop effective cancer therapies.

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Neuropilin-2 axis in regulating secretory phenotype of neuroendocrine-like prostate cancer cells and its implication in therapy resistance

Cited by 9 publications

References 68 publications

GD2 and its biosynthetic enzyme GD3 synthase promote tumorigenesis in prostate cancer by regulating cancer stem cell behavior

GD2 and its biosynthetic enzyme GD3 synthase promote tumorigenesis in prostate cancer by regulating cancer stem cell behavior

Identification of PRDX5 as A Target for The Treatment of Castration‐Resistant Prostate Cancer

Role of Neuropilin-2-mediated signaling axis in cancer progression and therapy resistance

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