Canonical Wnt Pathway Is Involved in Chemoresistance and Cell Cycle Arrest Induction in Colon Cancer Cell Line Spheroids

Moreno-Londoño, Ángela Patricia; Castañeda-Patlán, M. Cristina; Sarabia-Sánchez, Miguel Ángel; Macı́as-Silva, Marina; Robles-Flores, Martha

doi:10.3390/ijms24065252

Cited by 10 publications

(7 citation statements)

References 45 publications

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“…Given that in this study we found that mut-p53 activates β-catenin/Wnt signaling, and we have recently reported that canonical Wnt activation plays an essential role in inducing chemoresistance to 5-FU in colon cancer cells (Moreno-Londoño et al. 2023 ), we investigated whether mut-p53 could participate in the induction of chemoresistance to 5-FU. We found that endogenous expression of wtp53 explains the sensitivity to low doses in the RKO cell line, contrary to mutp53, where more concentration of 5-FU is needed to induce the same effect.…”

Section: Discussionmentioning

confidence: 85%

“…We recently reported that canonical Wnt activation plays an essential role in inducing chemoresistance to 5-Fluorouracil (5-FU) in colon cancer cells (Moreno-Londoño et al. 2023 ). Given that in this study, we found that mut-p53 activates β-catenin/Wnt signaling, we then investigated whether mut-p53 could also participate in this resistance induction.…”

Section: Resultsmentioning

confidence: 99%

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Mutant p53 gain-of-function stimulates canonical Wnt signaling via PI3K/AKT pathway in colon cancer

Alvarado-Ortiz,

Ortiz-Sánchez,

Sarabia-Sánchez

et al. 2023

J. Cell Commun. Signal.

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Aberrant canonical Wnt signaling is a hallmark of colon cancer. The TP53 tumor suppressor gene is altered in many solid tumors, including colorectal cancer, resulting in mutant versions of p53 (mut-p53) that lose their tumor suppressor capacities and acquire new-oncogenic functions (GOFs) critical for disease progression. Although the mechanisms related to mut-p53 GOF have been explored extensively, the relevance of mut-p53 in the canonical Wnt pathway is not well defined. This work investigated the influence of mut-p53 compared to wt-p53 in β-catenin-dependent Wnt signaling. Using the TCGA public data from Pan-Cancer and the GEPIA2 platform, an in silico analysis of wt-p53 versus mut-p53 genotyped colorectal cancer patients showed that TP53 (p53) and CTNNB1 (β-catenin) are significantly overexpressed in colorectal cancer, compared with normal tissue. Using p53 overexpression or p53 knockdown assays of wt-p53 or mut-p53, we found that while wt-p53 antagonizes canonical Wnt signaling, mut-p53 induces the opposite effect, improving the β-catenin-dependent transcriptional activity and colony formation ability of colon cancer cells, which were both decreased by mut-p53 knockdown expression. The mechanism involved in mut-p53-induced activation of canonical Wnt appears to be via AKT-mediated phosphorylation of Ser 552 of β-catenin, which is known to stabilize and enhance its transcriptional activity. We also found that while wt-p53 expression contributes to 5-FU sensitivity in colon cancer cells, the RITA p53 reactivating molecule counteracted the resistance against 5-FU in cells expressing mut-p53. Our results indicate that mut-p53 GOF acts as a positive regulator of canonical Wnt signaling and participates in the induction of resistance to 5-FU in colon cancer cells. Graphical abstract

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Section: Discussionmentioning

confidence: 85%

Section: Resultsmentioning

confidence: 99%

Mutant p53 gain-of-function stimulates canonical Wnt signaling via PI3K/AKT pathway in colon cancer

Alvarado-Ortiz,

Ortiz-Sánchez,

Sarabia-Sánchez

et al. 2023

J. Cell Commun. Signal.

Self Cite

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“…Association between stem cell molecules and their derived signals with the evolution of the tumorigenic process is widely accepted [26,27]. It has been proposed that intestinal stem cells represent an important part of the origin of CRC [28,29].…”

Section: Discussionmentioning

confidence: 99%

High OCT4 Expression Might Be Associated with an Aggressive Phenotype in Rectal Cancer

Lambis-Anaya

Fernández-Ruiz

Liscano

et al. 2023

Cancers

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Rectal cancer (RC) is one of the most common malignant neoplasms, and cancer stem cells (CSCs) of the intestinal tract have been implicated in its origin. The oncofetal protein OCT4 has been linked to neoplastic processes, but its role and clinical significance in RC are unknown. This study investigates the expression of the stem cell marker OCT4 related to clinical-pathological characteristics and its clinical significance in RC patients. The expression level of stem cell marker OCT4 was analyzed in 22 primary rectal tumors by western blot. The association between OCT4 protein expression and the clinical-pathological features of tumors was evaluated by χ2 test and Fisher’s exact test. We demonstrated that the expression of the stem cell marker OCT4 was observed in tumor tissue but not adjacent non-tumor tissue. High expression of the stem cell marker OCT4 was significantly associated with histological differentiation grade (p = 0.039), tumor invasion level (p = 0.004), lymph node involvement (p = 0.044), tumor-node-metastasis (TNM) stage (p = 0.002), and clinical stage (p = 0.021). These findings suggest that high OCT4 expression is associated with a more aggressive RC phenotype, with a greater likelihood of progression and metastasis. These results shed light on the importance of targeting this CSC marker to attenuate RC progression.

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“…For example, inhibitors of the Wnt/β-catenin pathway, such as PRI-724 and LGK974, have shown promise in preclinical studies. 50 – 52 Monoclonal antibodies : They target CSC-specific surface markers, such as CD133 and CD44, and have been developed. For example, a monoclonal antibody against CD133 (AC133) has been shown to reduce tumor growth and metastasis in preclinical models.…”

Section: Potential Therapeutic Strategies Targeting Cancer Stem Cells...mentioning

confidence: 99%

“…For example, inhibitors of the Wnt/β-catenin pathway, such as PRI-724 and LGK974, have shown promise in preclinical studies. 50 – 52 …”

Section: Potential Therapeutic Strategies Targeting Cancer Stem Cells...mentioning

confidence: 99%

Molecular Biomarkers and Signaling Pathways of Cancer Stem Cells in Colorectal Cancer

Omran,

Fouda,

Mekkawy

et al. 2024

Technol Cancer Res Treat

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Colorectal cancer (CRC) is the third most frequently found cancer in the world, and it is frequently discovered when it is already far along in its development. About 20% of cases of CRC are metastatic and incurable. There is more and more evidence that colorectal cancer stem cells (CCSCs), which are in charge of tumor growth, recurrence, and resistance to treatment, are what make CRC so different. Because we know more about stem cell biology, we quickly learned about the molecular processes and possible cross-talk between signaling pathways that affect the balance of cells in the gut and cancer. Wnt, Notch, TGF-β, and Hedgehog are examples of signaling pathway members whose genes may change to produce CCSCs. These genes control self-renewal and pluripotency in SCs and then decide the function and phenotype of CCSCs. However, in terms of their ability to create tumors and susceptibility to chemotherapeutic drugs, CSCs differ from normal stem cells and the bulk of tumor cells. This may be the reason for the higher rate of cancer recurrence in patients who underwent both surgery and chemotherapy treatment. Scientists have found that a group of uncontrolled miRNAs related to CCSCs affect stemness properties. These miRNAs control CCSC functions like changing the expression of cell cycle genes, metastasis, and drug resistance mechanisms. CCSC-related miRNAs mostly control signal pathways that are known to be important for CCSC biology. The biomarkers (CD markers and miRNA) for CCSCs and their diagnostic roles are the main topics of this review study.

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Canonical Wnt Pathway Is Involved in Chemoresistance and Cell Cycle Arrest Induction in Colon Cancer Cell Line Spheroids

Cited by 10 publications

References 45 publications

Mutant p53 gain-of-function stimulates canonical Wnt signaling via PI3K/AKT pathway in colon cancer

Mutant p53 gain-of-function stimulates canonical Wnt signaling via PI3K/AKT pathway in colon cancer

High OCT4 Expression Might Be Associated with an Aggressive Phenotype in Rectal Cancer

Molecular Biomarkers and Signaling Pathways of Cancer Stem Cells in Colorectal Cancer

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