Folic acid mediates activation of the pro-oncogene STAT3 via the Folate Receptor alpha

Hansen, Mariann Fagernæs; Greibe, Eva; Skovbjerg, Signe; Rohde, Sarah L.; Kristensen, Anders C. M.; Jensen, Trine R.; Stentoft, Charlotte; Kjær, Karina Hansen; Kronborg, C.; Martensen, Pia M.

doi:10.1016/j.cellsig.2015.03.020

Cited by 62 publications

(50 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, we sought to determine if tumor antigen-specific antibody response was enhanced in the combination treatment group. Folate receptor alpha (FRα) is a well-known tumor antigen that has been shown to be overexpressed in various epithelial derived cancer cells, including ovarian cancer, and deemed capable of driving oncogenic transformation (30). In order to determine if an antigen specific antibody response was generated, the sera from different treatment groups were assayed for FRα-specific antibodies.…”

Section: Resultsmentioning

confidence: 99%

IL10 Release upon PD-1 Blockade Sustains Immunosuppression in Ovarian Cancer

et al. 2017

View full text Add to dashboard Cite

Ligation of PD-1 in the tumor microenvironment is known to inhibit effective adaptive anti-tumor immunity. Blockade of PD-1 in humans has resulted in impressive, durable regression responses in select tumor types. However, durable responses have been elusive in ovarian cancer patients. PD-1 was recently shown to be expressed on and thereby impair the functions of tumor-infiltrating murine and human myeloid dendritic cells (TIDC) in ovarian cancer. In the present work, we characterize the regulation of PD-1 expression and the effects of PD-1 blockade on TIDC. Treatment of TIDC and bone marrow-derived DC with IL-10 led to increased PD-1 expression. Both groups of DC also responded to PD-1 blockade by increasing production of IL-10. Similarly, treatment of ovarian tumor-bearing mice with PD-1 blocking antibody resulted in an increase in IL-10 levels in both serum and ascites. While PD-1 blockade or IL-10 neutralization as monotherapies were inefficient, combination of these two led to improved survival and delayed tumor growth; this was accompanied by augmented anti-tumor T and B cell responses and decreased infiltration of immunosuppressive MDSC. Taken together, our findings implicate compensatory release of IL-10 as one of the adaptive resistance mechanisms that undermine the efficacy of anti-PD-1 (or anti-PD-L1) monotherapies and prompts further studies aimed at identifying such resistance mechanisms.

show abstract

Section: Resultsmentioning

confidence: 99%

IL10 Release upon PD-1 Blockade Sustains Immunosuppression in Ovarian Cancer

et al. 2017

View full text Add to dashboard Cite

show abstract

“…The addition of folates to cells activates intracellular signaling pathways in a FR-dependent manner in time periods that are shorter than would be expected from changes in one-carbon metabolism. The addition of folic acid to mammalian cells has been reported to induce the phospho-activation of c-src tyrosine kinase, ERK kinase, and STAT transcription factor in a FRα-dependent manner within 2–5 minutes of stimulation (Hansen et al, 2015; Lin et al, 2012; Zhang et al, 2009). Additionally, FRα itself has been reported to translocate to the nucleus and function as a transcription factor in human tissue culture cells after stimulation with 453 μM of folic acid (Boshnjaku et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Bacterial Folates Provide an Exogenous Signal for C. elegans Germline Stem Cell Proliferation

et al. 2016

View full text Add to dashboard Cite

Summary Here we describe an in vitro primary culture system for C. elegans germline stem cells. This culture system was used to identify a bacterial folate as a positive regulator of germ cell proliferation. Folates are a family of B-complex vitamins that function in one-carbon metabolism to allow the de novo synthesis of amino acids and nucleosides. We show that germ cell proliferation is stimulated by the folate 10-formyl-tetrahydrofolate-Glun both in vitro and in animals. Other folates that can act as vitamins to rescue folate deficiency lack this germ cell stimulatory activity. The bacterial folate precursor dihydropteroate also promotes germ cell proliferation in vitro and in vivo, despite its inability to promote one-carbon metabolism. The folate receptor homolog FOLR-1 is required for the stimulation of germ cells by 10-formyl-tetrahydrofolate-Glun and dihydropteroate. This work defines a folate and folate-related compound as exogenous signals to modulate germ cell proliferation.

show abstract

“…FRα overexpression has been reported to be associated with increased STAT3 signaling [23]. Hansen et al demonstrated that folate binding to FRα could induce STAT3 activation via a GP130 co-receptor-mediated JAK-dependent process [24]. Moreover, phosphorylated LYN tyrosine kinase was found in anti-FR mAb precipitates of FRα-expressing tumor cell lysates [25].…”

Section: Frα-mediated Internalization Of Folates and Regulation Of Camentioning

confidence: 99%

Targeting folate receptor alpha for cancer treatment

et al. 2016

View full text Add to dashboard Cite

Promising targeted treatments and immunotherapy strategies in oncology and advancements in our understanding of molecular pathways that underpin cancer development have reignited interest in the tumor-associated antigen Folate Receptor alpha (FRα). FRα is a glycosylphosphatidylinositol (GPI)-anchored membrane protein. Its overexpression in tumors such as ovarian, breast and lung cancers, low and restricted distribution in normal tissues, alongside emerging insights into tumor-promoting functions and association of expression with patient prognosis, together render FRα an attractive therapeutic target. In this review, we summarize the role of FRα in cancer development, we consider FRα as a potential diagnostic and prognostic tool, and we discuss different targeted treatment approaches with a specific focus on monoclonal antibodies. Renewed attention to FRα may point to novel individualized treatment approaches to improve the clinical management of patient groups that do not adequately benefit from current conventional therapies.

show abstract

Folic acid mediates activation of the pro-oncogene STAT3 via the Folate Receptor alpha

Cited by 62 publications

References 52 publications

IL10 Release upon PD-1 Blockade Sustains Immunosuppression in Ovarian Cancer

IL10 Release upon PD-1 Blockade Sustains Immunosuppression in Ovarian Cancer

Bacterial Folates Provide an Exogenous Signal for C. elegans Germline Stem Cell Proliferation

Targeting folate receptor alpha for cancer treatment

Contact Info

Product

Resources

About