CAMK2γ in intestinal epithelial cells modulates colitis-associated colorectal carcinogenesis via enhancing STAT3 activation

Ma, Xiaoxiao; Meng, Zhipeng; Jin, Lihua; Xiao, Zhenzhou; Wang, Xiaoqiong; Tsark, Walter; Ding, Lili; Gu, Ying; Zhang, Jiawei; Kim, Byungwook; He, Min; Gan, Xu; Shively, John E.; Yu, Hua; Xu, Rongzhen; Huang, Wendong

doi:10.1038/onc.2017.16

Cited by 29 publications

(25 citation statements)

References 69 publications

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“…Overexpression of pro-inflammatory cytokines is responsible for the induction of transcription factor nuclear factor kappa beta (NF-kβ) and hypoxia-inducible factor-1α (HIF-1α) [9,10]. Furthermore, overactivation of NF-κβ and HIF-1α leads to proliferation, migration, and invasion at the tumor site [11][12][13].…”

Section: Immunostaining Of P65 and Hif-1αmentioning

confidence: 99%

“…Some members of these families of compounds can modulate signaling pathways, as well as regulate the expression of genes involved in cell cycle regulation, differentiation, and apoptosis [8]. Chronic mucosal inflammation is the most common factor involved in both ulcerative colitis and colorectal cancer [9,10]. Overexpression of pro-inflammatory cytokines is responsible for the induction of transcription factor nuclear factor kappa beta (NF-κβ) and hypoxia-inducible factor-1α (HIF-1α) [11,12].…”

Section: Introductionmentioning

confidence: 99%

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Albumin Nano-Encapsulation of Piceatannol Enhances Its Anticancer Potential in Colon Cancer Via Downregulation of Nuclear p65 and HIF-1α

Aljabali

Bakshi

Hakkim

et al. 2020

Cancers

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Piceatannol (PIC) is known to have anticancer activity, which has been attributed to its ability to block the proliferation of cancer cells via suppression of the NF-kB signaling pathway. However, its effect on hypoxia-inducible factor (HIF) is not well known in cancer. In this study, PIC was loaded into bovine serum albumin (BSA) by desolvation method as PIC–BSA nanoparticles (NPs). These PIC–BSA nanoparticles were assessed for in vitro cytotoxicity, migration, invasion, and colony formation studies and levels of p65 and HIF-1α. Our results indicate that PIC–BSA NPs were more effective in downregulating the expression of nuclear p65 and HIF-1α in colon cancer cells as compared to free PIC. We also observed a significant reduction in inflammation induced by chemical colitis in mice by PIC–BSA NPs. Furthermore, a significant reduction in tumor size and number of colon tumors was also observed in the murine model of colitis-associated colorectal cancer, when treated with PIC–BSA NPs as compared to free PIC. The overall results indicate that PIC, when formulated as PIC–BSA NPs, enhances its therapeutic potential. Our work could prompt further research in using natural anticancer agents as nanoparticels with possible human clinical trails. This could lead to the development of a new line of safe and effective therapeutics for cancer patients.

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Section: Immunostaining Of P65 and Hif-1αmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Albumin Nano-Encapsulation of Piceatannol Enhances Its Anticancer Potential in Colon Cancer Via Downregulation of Nuclear p65 and HIF-1α

Aljabali

Bakshi

Hakkim

et al. 2020

Cancers

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“…It had been confirmed that STAT3 bound directly to the − 588 to − 800 bp region of IL-10 promoter to promote IL-10 transcription [30]. Ma et al found that dysregulation of CaMKII in intestinal epithelial cells regulated colitis-associated colorectal carcinogenesis by enhancing STAT3 activation [46]. Unudurthi et al showed that CaMKII was aberrantly activated in cardiac hypertrophy and heart failure, leading to degradation of βIV-spectrin, resulting in an increase of free STAT3 level [47].…”

Section: Discussionmentioning

confidence: 99%

Wnt5a-induced M2 polarization of tumor-associated macrophages via IL-10 promotes colorectal cancer progression

et al. 2020

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Background: Tumor-associated macrophages (TAMs) in the tumor microenvironment influence tumor initiation, invasion and metastasis. Several studies have shown that Wnt5a is mainly expressed in the tumor stroma, especially in TAMs. However, whether Wnt5a regulates the polarization and biological function of TAMs in colorectal cancer (CRC) is incompletely understood. Methods: Immunofluorescence staining was performed to detect CD68 and Wnt5a expression in colorectal tissues from patients (63 CRC specimens VS 20 normal tissues). RT-qPCR, flow cytometry, ELISA and inhibitors were carried out to explore the role of Wnt5a in the polarization of TAMs. Clone formation and transwell assays were performed to determine the effects of Wnt5a-treated macrophages on tumor proliferation, migration and invasion in vitro. Finally, a xenograft model was applied to confirm the effects of Wnt5a + TAMs on CRC tumorigenesis. Results: We found that high Wnt5a + CD68 + /CD68 + TAMs ratio was significantly associated with poor prognosis in CRC patients and Wnt5a + TAM was an M2-like TAM subtype. Subsequently, we found that Wnt5a induced macrophages to secrete IL-10, which then acted as an autocrine cytokine to induce M2 polarization of these macrophages. IL-10 neutralizing antibody completely reversed the pro-M2 effect of Wnt5a. Mechanistically, the CaKMII-ERK1/2-STAT3 pathway was required for Wnt5a-mediated IL-10 expression in macrophages. Furthermore, Wnt5a-induced M2 macrophages promoted CRC cells proliferation, migration and invasion; knockdown of Wnt5a in TAMs significantly impaired the pro-tumor functions of TAMs. Conclusions: Our data indicate that Wnt5a could induce M2 polarization of TAMs by regulating CaKMII-ERK1/2-STAT3 pathway-mediated IL-10 secretion, ultimately promoting tumor growth and metastasis of CRC.

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“…Part of the Ca 2+ signaling cascade, calmodulin kinase type II gamma (CaMKIIγ), plays an important role in tumor progression of prostate cancer by activation of AKT in a PI3K-independent manner [30], or in the development of colitis-associated cancer through activation of STAT3 [31]. Importantly, CaMKIIγ binds to c-Myc in a calcium-dependent manner [32] and phosphorylates c-Myc at Ser62 thereby increasing its stability and its half-life [11].…”

Section: Discussionmentioning

confidence: 99%

Phosphoenolpyruvate from Glycolysis and PEPCK Regulate Cancer Cell Fate by Altering Cytosolic Ca2+

Moreno-Felici

Hyroššová

Aragó

et al. 2019

Cells

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Changes in phosphoenolpyruvate (PEP) concentrations secondary to variations in glucose availability can regulate calcium signaling in T cells as this metabolite potently inhibits the sarcoplasmic reticulum Ca 2+ /ATPase pump (SERCA). This regulation is critical to assert immune activation in the tumor as T cells and cancer cells compete for available nutrients. We examined here whether cytosolic calcium and the activation of downstream effector pathways important for tumor biology are influenced by the presence of glucose and/or cataplerosis through the phosphoenolpyruvate carboxykinase (PEPCK) pathway, as both are hypothesized to feed the PEP pool. Our data demonstrate that cellular PEP parallels extracellular glucose in two human colon carcinoma cell lines, HCT-116 and SW480. PEP correlated with cytosolic calcium and NFAT activity, together with transcriptional up-regulation of canonical targets PTGS2 and IL6 that was fully prevented by CsA pre-treatment. Similarly, loading the metabolite directly into the cell increased cytosolic calcium and NFAT activity. PEP-stirred cytosolic calcium was also responsible for the calmodulin (CaM) dependent phosphorylation of c-Myc at Ser62, resulting in increased activity, probably through enhanced stabilization of the protein. Protein expression of several c-Myc targets also correlated with PEP levels. Finally, the participation of PEPCK in this axis was interrogated as it should directly contribute to PEP through cataplerosis from TCA cycle intermediates, especially in glucose starvation conditions. Inhibition of PEPCK activity showed the expected regulation of PEP and calcium levels and consequential downstream modulation of NFAT and c-Myc activities. Collectively, these results suggest that glucose and PEPCK can regulate NFAT and c-Myc activities through their influence on the PEP/Ca 2+ axis, advancing a role for PEP as a second messenger communicating metabolism, calcium cell signaling, and tumor biology.

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CAMK2γ in intestinal epithelial cells modulates colitis-associated colorectal carcinogenesis via enhancing STAT3 activation

Cited by 29 publications

References 69 publications

Albumin Nano-Encapsulation of Piceatannol Enhances Its Anticancer Potential in Colon Cancer Via Downregulation of Nuclear p65 and HIF-1α

Albumin Nano-Encapsulation of Piceatannol Enhances Its Anticancer Potential in Colon Cancer Via Downregulation of Nuclear p65 and HIF-1α

Wnt5a-induced M2 polarization of tumor-associated macrophages via IL-10 promotes colorectal cancer progression

Phosphoenolpyruvate from Glycolysis and PEPCK Regulate Cancer Cell Fate by Altering Cytosolic Ca2+

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