Surfactant Protein D as a Potential Biomarker and Therapeutic Target in Ovarian Cancer

Kumar, Juhi; Murugaiah, Valamarthy; Sotiriadis, Georgios; Kaur, Anuvinder; Jeyaneethi, Jeyarooban; Sturniolo, Isotta; Alhamlan, Fatimah S.; Chatterjee, Jayanta; Hall, Marcia; Kishore, Uday; Karteris, Emmanouíl

doi:10.3389/fonc.2019.00542

Cited by 18 publications

(19 citation statements)

References 48 publications

(62 reference statements)

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“…A direct interaction of SP-D with a number of cancer cells (leukemia, lung, prostate, and pancreatic) has been reported to result in the suppression of cancer progression, migration, and invasion, as well as enhanced apoptosis (17)(18)(19)(20)(21). The rfhSP-Dtreated acute myeloid leukemia (AML) cells were shown to result in cell cycle arrest via activation of G2/M checkpoints, with an increased level of p21 and Try15 phosphorylation of cdc2.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, rfhSP-D can also suppress epithelial-mesenchymal transition (EMT) and related gene signatures (Vimentin, Zeb1, and Snail) and cell invasiveness in Panc-1 and MiaPaCa-2 cells via downregulation of TGF-β (24). In an ovarian cell line, SKOV3, rfhSP-D again triggered apoptosis via the Fas-mediated pathway (18). In both pancreatic and ovarian cancer cell lines, rfhSP-D treatment caused activation of caspase 3 cleavage and induction of pro-apoptotic genes such as Fas and TNF-α.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, the mTOR pathway was also affected by rfhSP-D treatment in both ovarian and pancreatic cancer cell lines. rfhSP-D-treated SKOV3 cells show downregulation of Rictor and Raptor mRNA levels, suggesting inhibition of cell proliferation ( 17 , 18 ). Additionally, the anti-tumor role of rfhSP-D has been reported in androgen-resistant and androgen-responsive prostate cancer cells via p53 and pAkt pathways ( 19 ).…”

Section: Introductionmentioning

confidence: 99%

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Hyaluronic Acid Present in the Tumor Microenvironment Can Negate the Pro-apototic Effect of a Recombinant Fragment of Human Surfactant Protein D on Breast Cancer Cells

et al. 2020

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Human surfactant protein D (SP-D) belongs to the family of collectins that is composed of a characteristic amino-terminal collagenous region and a carboxy-terminal C-type lectin domain. Being present at the mucosal surfaces, SP-D acts as a potent innate immune molecule and offers protection against non-self and altered self, such as pathogens, allergens, and tumor. Here, we examined the effect of a recombinant fragment of human SP-D (rfhSP-D) on a range of breast cancer lines. Breast cancer has four molecular subtypes characterized by varied expressions of estrogen (ER), progesterone (PR), and epidermal growth factor (EGF) receptors (HER2). The cell viability of HER2-overexpressing (SKBR3) and triple-positive (BT474) breast cancer cell lines [but not of a triple-negative cell line (BT20)] was reduced following rfhSP-D treatment at 24 h. Upregulation of p21/p27 cell cycle inhibitors and p53 phosphorylation (Ser15) in rfhSP-D-treated BT474 and SKBR3 cell lines signified G2/M cell cycle arrest. Cleaved caspases 9 and 3 were detected in rfhSP-D-treated BT474 and SKBR3 cells, suggesting an involvement of the intrinsic apoptosis pathway. However, rfhSP-D-induced apoptosis was nullified in the presence of hyaluronic acid (HA) whose increased level in breast tumor microenvironment is associated with malignant tumor progression and invasion. rfhSP-D bound to solid-phase HA and promoted tumor cell proliferation. rfhSP-D-treated SKBR3 cells in the presence of HA showed decreased transcriptional levels of p53 when compared to cells treated with rfhSP-D only. Thus, HA appears to negate the anti-tumorigenic properties of rfhSP-D against HER2-overexpressing and triple-positive breast cancer cells.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hyaluronic Acid Present in the Tumor Microenvironment Can Negate the Pro-apototic Effect of a Recombinant Fragment of Human Surfactant Protein D on Breast Cancer Cells

et al. 2020

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“…In UV treated apoptotic Jurkat T cells, SP-D enhanced membrane and nuclear blebbing, suggesting involvement of SP-D in induction of apoptosis (16). Exogenous treatment of SKOV3 cells (an ovarian cancer cell line) with rfhSP-D led to increased caspase 3 cleavage and induction of pro-apoptotic genes Fas and TNF-α (17).…”

Section: Introductionmentioning

confidence: 99%

Human SP-D Acts as an Innate Immune Surveillance Molecule Against Androgen-Responsive and Androgen-Resistant Prostate Cancer Cells

et al. 2019

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Surfactant Protein D (SP-D), a pattern recognition innate immune molecule, has been implicated in the immune surveillance against cancer. A recent report showed an association of decreased SP-D expression in human prostate adenocarcinoma with an increased Gleason score and severity. In the present study, the SP-D expression was evaluated in primary prostate epithelial cells (PrEC) and prostate cancer cell lines. LNCaP, an androgen dependent prostate cancer cell line, exhibited significantly lower mRNA and protein levels of SP-D than PrEC and the androgen independent cell lines (PC3 and DU145). A recombinant fragment of human SP-D, rfhSP-D, showed a dose and time dependent binding to prostate cancer cells via its carbohydrate recognition domain. This study, for the first time, provides evidence of significant and specific cell death of tumor cells in rfhSP-D treated explants as well as primary tumor cells isolated from tissue biopsies of metatstatic prostate cancer patients. Viability of PrEC was not altered by rfhSP-D. Treated LNCaP (p53 +/+ ) and PC3 (p53 −/− ) cells exhibited reduced cell viability in a dose and time dependent manner and were arrested in G2/M and G1/G0 phase of the cell cycle, respectively. rfhSP-D treated LNCaP cells showed a significant upregulation of p53 whereas a significant downregulation of pAkt was observed in both PC3 and LNCaP cell lines. The rfhSP-D-induced apoptosis signaling cascade involved upregulation of Bax:Bcl2 ratio, cytochrome c and cleaved products of caspase 7. The study concludes that rfhSP-D induces apoptosis in prostate tumor explants as well as in androgen dependent and independent prostate cancer cells via p53 and pAkt pathways.

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“…As rfhSP-D is known to induce apoptosis in cancer and immortalised cells (18,(20)(21)(22), the effect of rfhSP-D on Vero cells was assessed using MTT assay. rfhSP-D treatment had no significant effect on the viability of Vero cells (Supplementary figure 3).…”

Section: Rfhsp-d Treatment Inhibits Sars-cov-2 Infection and Replicationmentioning

confidence: 99%

A recombinant fragment of Human surfactant protein D binds Spike protein and inhibits infectivity and replication of SARS-CoV-2 in clinical samples

Madan

Biswas

Varghese

et al. 2020

Preprint

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RationaleCOVID-19 is an acute infectious disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Human surfactant protein D (SP-D) is known to interact with spike protein of SARS-CoV, but its immune-surveillance against SARS-CoV-2 is not known.ObjectiveThis study aimed to examine the potential of a recombinant fragment of human SP-D (rfhSP-D) as an inhibitor of replication and infection of SARS-CoV-2.MethodsrfhSP-D interaction with spike protein of SARS-CoV-2 and hACE-2 receptor was predicted via docking analysis. The inhibition of interaction between spike protein and ACE-2 by rfhSP-D was confirmed using direct and indirect ELISA. The effect of rfhSP-D on replication and infectivity of SARS-CoV-2 from clinical samples was studied by measuring the expression of RdRp gene of the virus using qPCR.Measurements and Main ResultsIn-silico interaction studies indicated that three amino acid residues in the RBD of spike of SARS-CoV-2 were commonly involved in interacting with rfhSP-D and ACE-2. Studies using clinical samples of SARS-CoV-2 positive cases (asymptomatic, n=7 and symptomatic, n=8 and negative controls n=15) demonstrated that treatment with 5μM rfhSP-D inhibited viral replication by ~5.5 fold and was more efficient than Remdesivir (100 μM). Approximately, a 2-fold reduction in viral infectivity was also observed after treatment with 5μM rfhSP-D.ConclusionsThese results conclusively demonstrate that the calcium independent rfhSP-D mediated inhibition of binding between the receptor binding domain of the S1 subunit of the SARS-CoV-2 spike protein and human ACE-2, its host cell receptor, and a significant reduction in SARS-CoV-2 infection and replication in-vitro.

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Surfactant Protein D as a Potential Biomarker and Therapeutic Target in Ovarian Cancer

Cited by 18 publications

References 48 publications

Hyaluronic Acid Present in the Tumor Microenvironment Can Negate the Pro-apototic Effect of a Recombinant Fragment of Human Surfactant Protein D on Breast Cancer Cells

Hyaluronic Acid Present in the Tumor Microenvironment Can Negate the Pro-apototic Effect of a Recombinant Fragment of Human Surfactant Protein D on Breast Cancer Cells

Human SP-D Acts as an Innate Immune Surveillance Molecule Against Androgen-Responsive and Androgen-Resistant Prostate Cancer Cells

A recombinant fragment of Human surfactant protein D binds Spike protein and inhibits infectivity and replication of SARS-CoV-2 in clinical samples

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