Targeting the NF-κB Pathway as a Combination Therapy for Advanced Thyroid Cancer

Pozdeyev, Nikita; Berlinberg, Adam; Zhou, Qiong; Wuensch, Kelsey E.; Shibata, Hiroyuki; Wood, William M.; Haugen, Bryan R.

doi:10.1371/journal.pone.0134901

Cited by 33 publications

(24 citation statements)

References 30 publications

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“…This pathway appears to be constitutively activated in many types of human cancer including PTC. The NF-κB signaling pathway mediates multiple biological processes including inflammation, cellular proliferation, apoptosis, and invasion (Pozdeyev et al, 2015;Pagano et al, 2018). In addition, TNFα usually induces the NF-κB pathway in most cancers (Chowdhury et al, 2017;Zhou et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Notably, the pro-apoptotic and anti-proliferative effects of LDOC1 have been demonstrated in Jurkat, lymphoma, and pancreatic cancer (BxPC-3) cells, but not in cervical carcinoma or HeLa cells (Nagasaki et al, 2003;Inoue et al, 2005). In addition, nuclear factor-κB (NF-κB) signaling participates in various aspects of tumor biology (Capece et al, 2018) and this signaling pathway is constitutively activated in thyroid cancer (Pozdeyev et al, 2015;Pagano et al, 2018). Some anticancer drugs and ionizing radiation cause NF-κB activation, which, in turn, results in the development of treatment resistance (Pozdeyev et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, nuclear factor-κB (NF-κB) signaling participates in various aspects of tumor biology (Capece et al, 2018) and this signaling pathway is constitutively activated in thyroid cancer (Pozdeyev et al, 2015;Pagano et al, 2018). Some anticancer drugs and ionizing radiation cause NF-κB activation, which, in turn, results in the development of treatment resistance (Pozdeyev et al, 2015). The LDOC1 gene has been shown to inhibit ligand-induced NF-κB activity in pancreatic cancer cells (Nagasaki et al, 2003) and to downregulate Wnt/β-catenin signaling pathway in colorectal cancer cells (Jiang et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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LDOC1 is differentially expressed in thyroid cancer and display tumor‐suppressive function in papillary thyroid carcinoma

Zhao

Wang

et al. 2020

Cell Biology International

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The leucine zipper downregulated in cancer 1 (LDOC1) has been proposed as a regulator of transcription and cell signaling. We have previously demonstrated that LDOC1 is differentially expressed in papillary thyroid carcinoma (PTC), this study was designed to characterize LDOC1 expression in thyroid follicle originated cancer tissues and to specifically evaluate its function in thyroid carcinogenesis. LDOC1 expression was performed in human normal thyroid and thyroid cancer. LDOC1 function was characterized, in two PTC cell lines (TPC1 and BCPAP), through the analysis of in vitro cell proliferation, apoptosis, migration, and invasion along with in vivo tumor xenograft growth. Transduced BCPAP cells were stimulated with tumor necrosis factor α, and the levels of nuclear P65, Bax, Bcl‐2, c‐Myc, and XIAP were assessed. A luciferase reporter assay was used to measure nuclear factor‐κB (NF‐κB) activity, and the functional connection between LDOC1 effect and NF‐κB activity was determined using a specific NF‐κB inhibitor. Our results revealed that LDOC1 was translocated from the nucleus to the cytoplasm in human thyroid cancer, and was significantly downregulated in PTC compared with normal thyroid. LDOC1 overexpression in TPC1 resulted in a significant suppression of the malignant phenotype, whereas LDOC1 ablation in BCPAP promoted this phenotype. Additional studies demonstrated that LDOC1 ablation facilitated nuclear P65 expression and NF‐κB activity. NF‐κB inhibition reversed the effects of LDOC1 ablation on proliferation, apoptosis, migration, and invasion. Our findings confirmed that LDOC1 is a novel therapeutic target in PTC and provides new insight into the role of LDOC1 in PTC progression, through NF‐κΒ signaling suppression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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LDOC1 is differentially expressed in thyroid cancer and display tumor‐suppressive function in papillary thyroid carcinoma

Zhao

Wang

et al. 2020

Cell Biology International

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“…Together, these data indicated that miR-200a induced NF-κB activation through the targeting IκBα. Dysregulation of the NF-κB signaling pathway is well characterized in cancer cell proliferation, angiogenesis, migration and invasion (24,25); NF-κB signaling has been observed to be significantly activated in glioma, and the NF-κB pathway has been reported to significantly induce cancer cell proliferation and invasion in thyroid cancer. The current study provided further evidence of NF-κB activation in human NPC and investigated the association with miR-200a.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-200a mediates nasopharyngeal carcinoma cell proliferation through the activation of nuclear factor-κB

Shi

Chen

et al. 2015

Molecular Medicine Reports

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In nasopharyngeal carcinoma (NPC), the nuclear factor-κB (NF-κB) signaling pathway is highly active. The constitutive activation of NF-κB prompts malignant cell proliferation, and microRNAs are considered an important mediator in regulating the NF-κB signaling pathway. The current study investigated the effect of microRNA-200a (miR-200a) on NF-κB activation. Reverse transcription-quantitative polymerase chain reaction was used to quantify the relative level of miR-200a in NPC tissue samples and CNE2 cells. An MTT assay was used to investigate the effect of miR-200a on cell proliferation. To investigate the activation of NF-κB, western blotting was used to measure the protein levels of NF-κB and its downstream targets. To identify the target genes of miR-200a, a luciferase reporter assay was used. The current study demonstrated that miR-200a was upregulated in NPC tissue samples and cell lines. Overexpression of miR-200a resulted in the proliferation of CNE2 cells. Western blot analysis indicated that the protein levels of p65 increased when CNE2 cells were transfected with miR-200a mimics. Additionally, the downstream targets of miR-200a were upregulated, including vascular cell adhesion molecule, intercellular adhesion molecule and monocyte chemoattractant protein-1. The luciferase assay indicated that IκBα was the target gene of miR-200a. In conclusion, miR-200a was demonstrated to enhance NPC cell proliferation by activating the NF-κB signaling pathway.

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“…In vivo assays have demonstrated a reduction of tumor growth, but only in one cell line, diminishing the enthusiasm for this approach. Further research is needed to broadly apply this kind of treatment, combining conventional chemotherapy and novel targeted therapy to patients with advanced thyroid cancer [104].…”

Section: Chemotherapy Used In Combinationmentioning

confidence: 99%

Combinatorial Therapies in Thyroid Cancer: An Overview of Preclinical and Clinical Progresses

Gheysen

Saussez

Journé

2020

Cells

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Accounting for about 2% of cancers diagnosed worldwide, thyroid cancer has caused about 41,000 deaths in 2018. Despite significant progresses made in recent decades in the treatment of thyroid cancer, many resistances to current monotherapies are observed. In our complete review, we report all treatments that were tested in combination against thyroid cancer. Many preclinical studies investigating the effects of inhibitors of the MAPK and PI3K pathways highlighted the importance of mutations in such signaling pathways and their impacts on the subsequent efficacy of targeted therapies, thus reinforcing the need of more personalized therapeutic strategies. Our review also points out the multiple possibilities of combinatory strategies, particularly using therapies targeting proliferation, survival, angiogenesis, and in combination with conventional treatments such as chemotherapies. In any case, resistances to anticancer therapies always develop through the activation of alternative signaling pathways. Combinatory treatments aim to blockade such mechanisms, which are gradually decrypted, thus offering new perspectives for the future. The preclinical and clinical aspects of our review allow us to have a global opinion of the different therapeutic options currently evaluated in combination and to be aware about new perspectives of treatment of thyroid cancer.

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Targeting the NF-κB Pathway as a Combination Therapy for Advanced Thyroid Cancer

Cited by 33 publications

References 30 publications

LDOC1 is differentially expressed in thyroid cancer and display tumor‐suppressive function in papillary thyroid carcinoma

LDOC1 is differentially expressed in thyroid cancer and display tumor‐suppressive function in papillary thyroid carcinoma

MicroRNA-200a mediates nasopharyngeal carcinoma cell proliferation through the activation of nuclear factor-κB

Combinatorial Therapies in Thyroid Cancer: An Overview of Preclinical and Clinical Progresses

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