Roles of p53, NF-κB and the androgen receptor in controlling NGAL expression in prostate cancer cell lines

Chappell, William H.; Candido, Saverio; Abrams, Stephen L.; Russo, Suzanne; Ove, Roger; Martelli, Alberto M.; Cocco, Lucio; Ramazzotti, Giulia; Cervello, Melchiorre; Montalto, Giuseppe; Steelman, Linda S.; Leng, Xiaohong; Arlinghaus, Ralph B.; Libra, Massimo; McCubrey, James A.

doi:10.1016/j.jbior.2018.05.002

Cited by 21 publications

(20 citation statements)

References 105 publications

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“…In mice with breast cancer, the oncogene HER (for human epidermal growth factor receptor) induces LCN2 expression and antibody-mediated blockade by trastuzumab antagonizes this effect ( 186 ). In prostate cancer cells, NF-κB as well as mutation or loss of p53 result in enhanced LCN2 expression ( 187 ). In addition, pro-inflammatory cytokines, such as TNF, IL-1ß, and IL-17 stimulate LCN2 expression via NF-κB ( 188 , 189 ).…”

Section: A Quadriga Of Iron-binding Proteins Is Present In Plasmamentioning

confidence: 99%

Iron in the Tumor Microenvironment—Connecting the Dots

et al. 2018

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Iron metabolism and tumor biology are intimately linked. Iron facilitates the production of oxygen radicals, which may either result in iron-induced cell death, ferroptosis, or contribute to mutagenicity and malignant transformation. Once transformed, malignant cells require high amounts of iron for proliferation. In addition, iron has multiple regulatory effects on the immune system, thus affecting tumor surveillance by immune cells. For these reasons, inconsiderate iron supplementation in cancer patients has the potential of worsening disease course and outcome. On the other hand, chronic immune activation in the setting of malignancy alters systemic iron homeostasis and directs iron fluxes into myeloid cells. While this response aims at withdrawing iron from tumor cells, it may impair the effector functions of tumor-associated macrophages and will result in iron-restricted erythropoiesis and the development of anemia, subsequently. This review summarizes our current knowledge of the interconnections of iron homeostasis with cancer biology, discusses current clinical controversies in the treatment of anemia of cancer and focuses on the potential roles of iron in the solid tumor microenvironment, also speculating on yet unknown molecular mechanisms.

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Section: A Quadriga Of Iron-binding Proteins Is Present In Plasmamentioning

confidence: 99%

Iron in the Tumor Microenvironment—Connecting the Dots

et al. 2018

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“…Neutrophil gelatinase-associated lipocalin (NGAL) is capable of forming covalently linked complexes, both in monomeric and dimeric modes, with matrix metalloproteinase-9 (MMP-9) and is sometimes considered an accessory protein of MMP-9. NGAL is expressed at higher levels in AR- negative DU145 and PC3 cells than in AR+ 22v-1 and LNCaP cells [ 14 ]. The presence of WT-TP53 did not alter the expression of NGAL in either DU145 or PC3 cells as determined by RT-PCR.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, DDR1 was expressed at higher levels in cells with functional WT TP53 activity, while NGAL is expressed at lower levels in cells with functional TP53. Both DDR1 and NGAL have effects on and regulated by collagen and the ECM [ 7 – 9 , 14 , 15 ].…”

Section: Resultsmentioning

confidence: 99%

“…We chose to examine the effects of DDR1b expression in PC3 cells as they lack WT TP53, AR and PTEN activity and have high levels of activated Akt but very low levels of ERK1,2 pathway activation due to elevated Akt activity in these cells [ 16 ]. Previously we determined that PC3 cells expressed high levels of NGAL and MMP9 and that suppression of NGAL inhibited the colony formation of the cells in soft agar [ 14 ]. In this current study, we observed that introduction of DDR1 into PC3 cells increased their chemosensitivity.…”

Section: Discussionmentioning

confidence: 99%

“…LNCaP, 22Rv-1, DU145 and PC3 cells were purchased from the ATCC (Rockville, MD, USA) and maintained in RPMI + 10% fetal bovine serum (FBS) (Atlanta Biologicals, Atlanta, GA, USA) and antibiotics (Atlanta Biologicals) as described previously [ 5 , 6 , 14 ]. Gelatin was purchased from Invitrogen (Carlsbad, CA)…”

Section: Methodsmentioning

confidence: 99%

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Influences of TP53 and the anti-aging DDR1 receptor in controlling Raf/MEK/ERK and PI3K/Akt expression and chemotherapeutic drug sensitivity in prostate cancer cell lines

Chappell

Candido

Abrams

et al. 2020

Aging

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Background: TP53 plays critical roles in sensitivity to chemotherapy, and aging. Collagen is very important in aging. The molecular structure and biochemical properties of collagen changes during aging. The discoidin domain receptor (DDR1) is regulated in part by collagen. Elucidating the links between TP53 and DDR1 in chemosensitivity and aging could improve therapies against cancer and aging. Results: Restoration of WT-TP53 activity resulted in increased sensitivity to chemotherapeutic drugs and elevated expression of key components of the Raf/MEK/ERK, PI3K/Akt and DDR1 pathways. DDR1 could modulate the levels of Raf/MEK/ERK and PI3K/Akt pathways as well as sensitize the cells to chemotherapeutic drugs. In contrast, suppression of WT TP53 with a dominant negative (DN) TP53 gene, suppressed DDR1 protein levels and increased their chemoresistance. Conclusion: Restoration of WT TP53 activity or increased expression of the anti-aging DDR1 collagen receptor can result in enhanced sensitivity to chemotherapeutic drugs. Our innovative studies indicate the important links between WT TP53 and DDR1 which can modulate Raf/MEK/ERK and PI3K/Akt signaling as well as chemosensitivity and aging. Methods: We investigated the roles of wild type (WT) and mutant TP53 on drug sensitivity of prostate cancer cells and the induction of Raf/MEK/ERK, PI3K/Akt and DDR1 expression and chemosensitivity.

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