Signaling pathways involved in colorectal cancer progression

Koveitypour, Zahra; Panahi, Farnoush; Vakilian, Mehrdad; Peymani, Maryam; Forootan, Farzad Seyed; Nasr-Esfahani, Mohammad Hossein; Ghaedi, Kamran

doi:10.1186/s13578-019-0361-4

Cited by 232 publications

(171 citation statements)

References 68 publications

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“…The oncogenic signaling pathways ranked high, i.e. classical MAPK and PI3K-AKT pathways, were given primary attention in the downregulated signaling pathways revealed by RNA-seq, which were demonstrated to be important signaling pathways in CRC (52). Activation of the PI3K-AKT signaling pathway regulates multiple biological processes, such as promoting invasion and metastasis of CRC (53).…”

Section: Discussionmentioning

confidence: 99%

Cyclovirobuxine D inhibits colorectal cancer tumorigenesis via the CTHRC1‑AKT/ERK‑Snail signaling pathway

et al. 2020

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Cyclovirobuxine D (CVB-D) is an alkaloid, which is mainly derived from Buxus microphylla. It has been reported that CVB-D has positive effects on breast cancer, gastric cancer and other malignant tumors. However, to the best of our knowledge, there are no reports regarding the effects of CVB-D on colorectal cancer (CRC). The purpose of the present study was to determine the anticancer effects of CVB-D and further elucidate its molecular mechanism(s). DLD-1 and LoVo cell lines were selected to evaluate the antitumor effect of CVB-D. Cytotoxicity, viability and proliferation were evaluated by the MTT and colony formation assays. Flow cytometry was used to detect the effects on apoptosis and the cell cycle in CVB-D-treated CRC cells. The migration and invasion abilities of CRC cells were examined by wound healing and Transwell assays. In addition, RNA sequencing, bioinformatics analysis and western blotting were performed to investigate the target of drug action and clarify the molecular mechanisms. A xenograft model was established using nude mice, and ultrasound was employed to assess the preclinical therapeutic effects of CVB-D in vivo. It was identified that CVB-D inhibited the proliferation, migration, stemness, angiogenesis and epithelial-mesenchymal transition of CRC cells, and induced apoptosis and S-phase arrest. In addition, CVB-D significantly inhibited the growth of xenografts. It is notable that CVB-D exerted anticancer effects in CRC cells partly by targeting collagen triple helix repeat containing 1 (CTHRC1), which may be upstream of the AKT and ERK pathways. CVB-D exerted anticancer effects through the CTHRC1-AKT/ERK-Snail signaling pathway. Targeted therapy combining CTHRC1 with CVB-D may offer a promising novel therapeutic approach for CRC treatment.

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Section: Discussionmentioning

confidence: 99%

Cyclovirobuxine D inhibits colorectal cancer tumorigenesis via the CTHRC1‑AKT/ERK‑Snail signaling pathway

et al. 2020

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“…PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2) to yield phosphatidylinositol 3,4,5-triphosphate (PIP3) and synthesis of this lipids leads to the recruitment of the serine/threonine kinase Akt, synonymously called protein kinase B (PKB), the downstream target of PI3K ( Figure 3 B). Phosphorylation of Akt by the phosphoinositide dependent protein kinase 1 (PDK1) functionally associated with tumor growth and inhibition of apoptosis is also relevant for EMT ( Figure 3 B) [ 13 , 122 ]. The PI3K pathway is antagonized by intrinsic inhibitors including the lipid phosphatase and tensin homologue protein (PTEN) which dephosphorylates PIP3 to PIP2 ( Figure 3 B).…”

Section: Diverse Oncogenic Signaling Pathways Are Affected By Trimmentioning

confidence: 99%

“…Interestingly, mutations in the Apc gene were not exclusively found in FAP patients, but also in many sporadic colorectal tumors [ 11 , 12 ]. Besides the Wnt/β-catenin signaling pathway other signaling cascades critical for keeping the integrity of the intestine including the transforming growth factor β (TGFβ)-Smad signaling module, the phospho i nositide-3 (PI3)- and Akt kinases, the K-ras oncogene, or those driven by the tumor suppressor p53 are frequently altered in sporadic CRC [ 13 ]. In addition, a large fraction of CRC tumors exhibit a constitutive activation of prominent pro-inflammatory signaling pathways, such as signal transducer and activator of transcription 3 (STAT3) and nuclear factor κB (NF-κB) [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Multifaceted Roles of TRIM Proteins in Colorectal Carcinoma

Eberhardt

Haeussler

Nasrullah

et al. 2020

IJMS

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Colorectal cancer (CRC) is one of the most frequently diagnosed tumor in humans and one of the most common causes of cancer-related death worldwide. The pathogenesis of CRC follows a multistage process which together with somatic gene mutations is mainly attributed to the dysregulation of signaling pathways critically involved in the maintenance of homeostasis of epithelial integrity in the intestine. A growing number of studies has highlighted the critical impact of members of the tripartite motif (TRIM) protein family on most types of human malignancies including CRC. In accordance, abundant expression of many TRIM proteins has been observed in CRC tissues and is frequently correlating with poor survival of patients. Notably, some TRIM members can act as tumor suppressors depending on the context and the type of cancer which has been assessed. Mechanistically, most cancer-related TRIMs have a critical impact on cell cycle control, apoptosis, epithelial–mesenchymal transition (EMT), metastasis, and inflammation mainly through directly interfering with diverse oncogenic signaling pathways. In addition, some recent publications have emphasized the emerging role of some TRIM members to act as transcription factors and RNA-stabilizing factors thus adding a further level of complexity to the pleiotropic biological activities of TRIM proteins. The current review focuses on oncogenic signaling processes targeted by different TRIMs and their particular role in the development of CRC. A better understanding of the crosstalk of TRIMs with these signaling pathways relevant for CRC development is an important prerequisite for the validation of TRIM proteins as novel biomarkers and as potential targets of future therapies for CRC.

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“…Upon Wnt interaction with receptors, the intracellular signal is transduced with the recruitment of cytoplasmic Disheveled phosphoproteins (Dvl) to membranes and this provides a site for Axis Inhibitor (AXIN) and Glycogen Synthase Kinase-3 (GSK3β) to bind and phosphorylate LRP5/6, thus preventing the constitutive degradation of β-Catenin [ 5 ]. Intracellular Wnt/β-Catenin signaling depends on the amount of the transcriptional co-activator β-Catenin, which migrates from the cytoplasm to the nucleus to engage the T cell Transcription Factor (TCF) or the Lymphoid Enhancer Factor (LEF) regulating the expression of several target genes involved in key cellular processes, such as c-Myc , cyclin D1 , and CD44 [ 6 , 7 ]. In the absence of Wnt ligands, β-Catenin is degraded through phosphorylation and ubiquitination by a multimeric protein complex, known as destruction complex, consisting of several proteins, as Adenomatous Polyposis Coli (APC), AXIN, Casein Kinase 1 (CK1), and GSK3β [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…Given its relevance in cellular homeostasis, the aberrant activation of Wnt pathway is a key mechanism in human colorectal carcinogenesis [ 7 ]. Aberrant mutations in Wnt pathway components have been identified in about 90% of human CRCs, especially inactivating APC mutations or activating β-Catenin mutations, resulting in enhanced transcription of genes involved in cellular proliferation and tumor progression [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

TRAP1 Regulates Wnt/β-Catenin Pathway through LRP5/6 Receptors Expression Modulation

Lettini

Condelli

Pietrafesa

et al. 2020

IJMS

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Wnt/β-Catenin signaling is involved in embryonic development, regeneration, and cellular differentiation and is responsible for cancer stemness maintenance. The HSP90 molecular chaperone TRAP1 is upregulated in 60–70% of human colorectal carcinomas (CRCs) and favors stem cells maintenance, modulating the Wnt/β-Catenin pathway and preventing β-Catenin phosphorylation/degradation. The role of TRAP1 in the regulation of Wnt/β-Catenin signaling was further investigated in human CRC cell lines, patient-derived spheroids, and CRC specimens. TRAP1 relevance in the activation of Wnt/β-Catenin signaling was highlighted by a TCF/LEF Cignal Reporter Assay in Wnt-off HEK293T and CRC HCT116 cell lines. Of note, this regulation occurs through the modulation of Wnt ligand receptors LRP5 and LRP6 that are both downregulated in TRAP1-silenced cell lines. However, while LRP5 mRNA is significantly downregulated upon TRAP1 silencing, LRP6 mRNA is unchanged, suggesting independent mechanisms of regulation by TRAP1. Indeed, LRP5 is regulated upon promoter methylation in CRC cell lines and human CRCs, whereas LRP6 is controlled at post-translational level by protein ubiquitination/degradation. Consistently, human CRCs with high TRAP1 expression are characterized by the co-upregulation of active β-Catenin, LRP5 and LRP6. Altogether, these data suggest that Wnt/β-Catenin signaling is modulated at multiple levels by TRAP1.

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Signaling pathways involved in colorectal cancer progression

Cited by 232 publications

References 68 publications

Cyclovirobuxine D inhibits colorectal cancer tumorigenesis via the CTHRC1‑AKT/ERK‑Snail signaling pathway

Cyclovirobuxine D inhibits colorectal cancer tumorigenesis via the CTHRC1‑AKT/ERK‑Snail signaling pathway

Multifaceted Roles of TRIM Proteins in Colorectal Carcinoma

TRAP1 Regulates Wnt/β-Catenin Pathway through LRP5/6 Receptors Expression Modulation

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