RAC1b overexpression stimulates proliferation and NF-kB-mediated anti-apoptotic signaling in thyroid cancer cells

Faria, Márcia; Matos, Paulo; Pereira, Teresa; Cabrera, Rafael; Cardoso, Bruno; Bugalho, Maria João; Silva, Ana Luísa

doi:10.1371/journal.pone.0172689

Cited by 23 publications

(18 citation statements)

References 29 publications

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“…Rac1b has been associated with poor prognosis in KRAS/BRAF WT metastatic colorectal cancer patients treated with first-line FOLFOX/XELOX therapy (41). Previous studies demonstrate that Rac1b stimulates cell proliferation by enhancing the NF-kB-mediated signaling in colorectal and thyroid cancer cells (12,13,24,42). In our study, we also showed that Rac1b expression provides a proliferative advantage to colorectal cancer cells via activation of the NF-kB pathway.…”

Section: Discussionsupporting

confidence: 77%

“…Colorectal cancer cell lines with acquired resistance to OXA showed increased activation of NF-kB in comparison to their matched sensitive parental cells, implicating NF-kB as a significant mediator of OXA resistance in these cells (53,54). Our data and others have shown that Rac1b expression activates the NF-kB signaling pathway in colon, lung, and thyroid cancer (12,13,24). Interestingly, we showed that OXA treatment results in upregulation of Rac1b, which leads to further enhanced NF-kB-mediated signaling and a significant shift in the sensitivity to chemotherapeutic agents.…”

Section: Discussionsupporting

confidence: 60%

“…This insertion greatly reduces the intrinsic GTPase activity of Rac1b and impairs sequestration by RhoGDIs, resulting in Rac1b being preferentially found in a GTP-bound, active form (10). Although Rac1 activation strongly activates conical downstream signaling through p21-activated kinases (PAK) or Jun N-terminal kinase (JNK), Rac1b has been shown to poorly activate PAK and JNK (11).Instead, Rac1b has been shown to facilitate the proliferation of lung and colon cancer cells, via NF-kB pathway, and inducing Cyclin D1 expression (12,13). The expression of Rac1b in fibroblasts stimulated cell-cycle progression and survival under conditions of serum starvation (14).…”

Section: Introductionmentioning

confidence: 99%

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RAC1b Overexpression Confers Resistance to Chemotherapy Treatment in Colorectal Cancer

Goka¹,

Chaturvedi²,

Lopez³

et al. 2019

Molecular Cancer Therapeutics

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Resistance to chemotherapy represents a major limitation in the treatment of colorectal cancer. Novel strategies to circumvent resistance are critical to prolonging patient survival. Rac1b, a constitutively activated isoform of the small GTPase Rac1, is upregulated with disease progression and promotes cell proliferation and inhibits apoptosis by activation of NF-kB signaling. Here, we show that Rac1b overexpression correlates with cancer stage and confirmed Rac1b expression is associated with increased growth through enhancing NF-kB activity. Rac1b knockdown reduced cellular proliferation and reduced NF-kB activity. Surprisingly, Rac1b expression and NF-kB activity were upregulated in cells treated with chemotherapeutics, suggesting that Rac1b facilitates chemo-resistance through activation of NF-kB signaling. Knockdown of Rac1b or Rac inhibition increases the sensitivity of the cells to oxaliplatin. When used in combination, inhibition of Rac prevents the increase in NF-kB activity associated with chemotherapy treatment and increases the sensitivity of the cells to oxaliplatin. Although Rac inhibition or oxaliplatin treatment alone reduces the growth of colorectal cancer in vivo, combination therapy results in improved outcomes compared with single agents alone. We provide the first evidence that Rac1b expression confers resistance to chemotherapy in colorectal cancer. Additionally, we show that the use of a Rac inhibitor prevents chemoresistance by blocking activation of chemotherapy induced NF-kB signaling, providing a novel strategy to overcome resistance to chemotherapy in colorectal cancer.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionsupporting

confidence: 60%

Section: Introductionmentioning

confidence: 99%

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RAC1b Overexpression Confers Resistance to Chemotherapy Treatment in Colorectal Cancer

Goka¹,

Chaturvedi²,

Lopez³

et al. 2019

Molecular Cancer Therapeutics

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“…Increased NF-kB activation has been described in PTC, FTC and anaplastic TC, as being associated with resistance to apoptosis and maintenance of the malignant phenotype [14][15][16]. Also, in previous studies, we have shown that overexpression of tumor-related RAC1b, a highly activated splice variant of the GTPase RAC1 [17,18], has a significant role in PTC tumorigenesis by inducing resistance to programmed cell death through NF-κB activation [19].…”

Section: Introductionmentioning

confidence: 57%

“…NF-κB family of transcription factors is responsible for regulating many cellular processes such as inflammatory responses, cellular growth and cell death, and has been also implicated in TC development. We have previously reported NF-kB activation as a key mechanism through which the tumor-related RAC1b exerts its oncogenic action in the context of PTC [19]. Additionally, we have also recently shown an inverse correlation between RAC1b overexpression and NIS levels in DTCs [45].…”

Section: Fig 3 Effect Of Tnf-α and Pma On Tsh-induced Iodide Uptake mentioning

confidence: 72%

TNFα-mediated activation of NF-κB downregulates sodium-iodide symporter expression in thyroid cells

et al. 2020

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The sodium-iodide symporter (NIS) mediates transport of iodide across the basolateral membrane of thyroid cells. NIS expression in thyroid cancer (TC) cells allows the use of radioactive iodine (RAI) as a diagnostic and therapeutic tool, being RAI therapy the systemic treatment of choice for metastatic disease. Still, a significant proportion of patients with advanced TC lose the ability to respond to RAI therapy and no effective alternative therapies are available. Defective NIS expression is the main reason for impaired iodide uptake in TC and NIS downregulation has been associated with several pathways linked to malignant transformation. NF-κB signaling is one of the pathways associated with TC. Interestingly, NIS expression can be negatively regulated by TNF-α, a bona fide activator of NF-κB with a central role in thyroid autoimmunity. This prompted us to clarify NF-kB's role in this process. We confirmed that TNF-α leads to downregulation of TSH-induced NIS expression in non-neoplastic thyroid follicular cell-derived models. Notably, a similar effect was observed when NF-κB activation was triggered independently of ligand-receptor specificity, using phorbol-myristate-acetate (PMA). TNF-α and PMA downregulation of NIS expression was reverted when NF-κB-dependent transcription was blocked, demonstrating the requirement for NF-kB activity. Additionally, TNF-α and PMA were shown to have a negative impact on TSH-induced iodide uptake, consistent with the observed transcriptional downregulation of NIS. Our data support the involvement of NF-κB-directed transcription in the modulation of NIS expression, where up-or down-regulation of NIS depends on the combined output to NF-κB of several converging pathways. A better understanding of the mechanisms underlying NIS expression in the context of normal thyroid physiology may guide the development of pharmacological strategies to increase the efficiency of iodide uptake. Such strategies would be extremely useful in improving the response to RAI therapy in refractory-TC.

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The role of small GTPases of the Rho/Rac family in TGF‐β‐induced EMT and cell motility in cancer

Ungefroren

Witte

Lehnert

2017

Developmental Dynamics

107

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This article focuses on the role of Rho family GTPases, particularly Rac1 and Rac1b in TGF-b-induced epithelial-mesenchymal transition (EMT) and EMT-associated responses such as cell migration, invasion, and metastasis in cancer. EMT is considered a prerequisite for cells to adopt a motile and invasive phenotype and eventually become metastatic. A major regulator of EMT and metastasis in cancer is TGF-b, and its specific functions on tumor cells are mediated beside Smad proteins and mitogenactivated protein kinases (MAPKs) by small GTPases of the Rho/Rac1 family. Available data point to extensive signaling crosstalk between TGF-b and various Rho GTPases, and in particular a synergistic role of Rho and Rac1 during EMT and cell motility in normal and neoplastic epithelial cells. In contrast, the Rac1-related isoform, Rac1b, emerges as an endogenous inhibitor of Rac1 in TGF-b signaling, at least in pancreatic carcinoma cells. Given the tumor-promoting role of TGF-b in late-stage carcinomas and the intimate crosstalk of Rho/Rac1/Rac1b and TGF-b signaling in various tumor cell responses, targeting specific Rho GTPases may allow for selective interference with prooncogenic TGF-b responses to aid in anticancer treatments. Developmental Dynamics 247:451-461,

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RAC1b overexpression stimulates proliferation and NF-kB-mediated anti-apoptotic signaling in thyroid cancer cells

Cited by 23 publications

References 29 publications

RAC1b Overexpression Confers Resistance to Chemotherapy Treatment in Colorectal Cancer

RAC1b Overexpression Confers Resistance to Chemotherapy Treatment in Colorectal Cancer

TNFα-mediated activation of NF-κB downregulates sodium-iodide symporter expression in thyroid cells

The role of small GTPases of the Rho/Rac family in TGF‐β‐induced EMT and cell motility in cancer

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