Effect of 5‐fluorouracil on excision repair cross‐complementing 1 expression and consequent cytotoxicity regulation in human gastric cancer cells

Liu, Jinglan; Huang, Wen‐Shih; Lee, Ko‐Chao; Tung, Shui‐Yi; Chen, Cheng‐Nan; Chang, Shun‐Fu

doi:10.1002/jcb.27073

Cited by 10 publications

(8 citation statements)

References 30 publications

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“…Molecularly, the p38 MAPK activation has been previously reported to induce pro-survival effects, upon etoposide treatment in NSCLC 23 and 5-FU in gastric cancer 24 , via upregulation of excision repair cross-complementary 1 (ERCC1) protein, one of the critical proteins involved in nuclear excision repair (NER). Hence, we investigated whether in CRC lines the ERCC1 upregulation might constitute one of the pro-survival cues downstream of MKK3/p38delta MAPK signaling cascade.…”

Section: Resultsmentioning

confidence: 99%

MKK3 sustains cell proliferation and survival through p38DELTA MAPK activation in colorectal cancer

et al. 2019

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Colorectal cancer (CRC) is one of the most common malignant tumors worldwide and understanding its underlying molecular mechanisms is crucial for the development of therapeutic strategies. The mitogen-activated protein kinase-kinase 3 (MKK3) is a specific activator of p38 MAP kinases (p38 MAPKs), which contributes to the regulation of several cellular functions, such as proliferation, differentiation, apoptosis as well as response to drugs. At present, the exact MKK3/p38 MAPK pathway contribution in cancer is heavily debated because of its pleiotropic function. In this work, we retrospectively explored the prognostic and pathobiologic relevance of MKK3 in a cohort of CRC patients and assessed MKK3 molecular functions in a panel of CRC lines and colonocytes primary cultures. We found increased MKK3 levels in late-stage CRC patients which correlated with shorter overall survival. Herein, we report that the MKK3 targeting by inducible RNA interference univocally exerts antitumor effects in CRC lines but not in primary colonocytes. While MKK3 depletion per se affects growth and survival by induction of sustained autophagy and death in some CRC lines, it potentiates response to chemotherapeutic drug 5-fluorouracil (5-FU) in all of the tested CRC lines in vitro. Here, we demonstrate for the first time that in CRC the MKK3 specifically activates p38delta MAPK isoform to sustain prosurvival signaling and that such effect is exacerbated upon 5-FU challenge. Indeed, p38delta MAPK silencing recapitulates MKK3 depletion effects in CRC cells in vitro and in vivo. Overall, our data identified a molecular mechanism through which MKK3 supports proliferation and survival signaling in CRC, further supporting MKK3 as a novel and extremely attractive therapeutic target for the development of promising strategies for the management of CRC patients.

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Section: Resultsmentioning

confidence: 99%

MKK3 sustains cell proliferation and survival through p38DELTA MAPK activation in colorectal cancer

et al. 2019

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“…The effects of 5-FU on molecular stress pathways have long been investigated: indeed, reports are quite unanimous about p38 MAPK being phosphorylated and activated upon 5-FU exposure in several different cell-types [23,24]. However, when it comes to the final biological outcome of 5-FU-induced p38 MAPK activation, reports are contradictive, assessing roles in both wild type p53 (wt-p53) mediated activation and apoptosis [25,26] or mediating prosurvival signaling via activation of DNA repair or antiapoptotic proteins [27,28]. Overall, the cellular context and interaction with other signaling pathways skew p38 MAPK signaling [5].…”

Section: -Fluorouracil Effects On the P38 Mapk Signaling Pathway In Crcmentioning

confidence: 99%

The p38 MAPK Signaling Activation in Colorectal Cancer upon Therapeutic Treatments

Pranteda¹,

Piastra²,

Stramucci³

et al. 2020

IJMS

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Pharmacological treatment of colorectal carcinoma currently proceeds through the administration of a combination of different chemotherapeutic agents. In the case of rectal carcinoma, radiation therapy also represents a therapeutic strategy. In an attempt at translating much-needed new targeted therapy to the clinics, p38 mitogen activated protein kinase (MAPK) inhibitors have been tested in clinical trials involving colorectal carcinoma patients, especially in combination with chemotherapy; however, despite the high expectations raised by a clear involvement of the p38 MAPK pathway in the response to therapeutic treatments, poor results have been obtained so far. In this work, we review recent insights into the exact role of the p38 MAPK pathway in response to currently available therapies for colorectal carcinoma, depicting an intricate scenario in which the p38 MAPK node presents many opportunities, as well as many challenges, for its perspective exploitation for clinical purposes.

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“…that the acquired upregulation of the excision repair cross‐complementing 1 (ERCC1), a component of the NER system, was induced by 5‐FU treatment in gastric cancer cells, which can subsequently weaken the anticancer activity of 5‐FU. Further mechanism studies revealed that 5‐FU‐induced ERCC1 overexpression may be regulated by ERK 1/2 and p38 signaling‐mediated activation of the transcription factor c‐jun/activator protein‐1, which provides a clue to overcome this resistance mechanism using ERK inhibitors or p38 kinase inhibitors 198 . In contrast, the role of MMR in 5‐FU resistance remains uncertain.…”

Section: Resistance Mechanisms In Cancer and Combating Strategiesmentioning

confidence: 99%

“…Further mechanism studies revealed that 5-FU-induced ERCC1 overexpression may be regulated by ERK 1/2 and p38 signaling-mediated activation of the transcription factor cjun/activator protein-1, which provides a clue to overcome this resistance mechanism using ERK inhibitors or p38 kinase inhibitors. 198 In contrast, the role of MMR in 5-FU resistance remains uncertain. It was recently reported by Oliver et al that both MMR-proficient and MMR-deficient CRC cells exhibited 5-FU resistance after a period of treatment, suggesting that 5-FU chemoresistance in CRC cells may be independent of MMR status.…”

Section: Enhanced Dna Repairmentioning

confidence: 99%

Understanding and targeting resistance mechanisms in cancer

Lei

Teng

Wurpel

et al. 2023

MedComm

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Resistance to cancer therapies has been a commonly observed phenomenon in clinical practice, which is one of the major causes of treatment failure and poor patient survival. The reduced responsiveness of cancer cells is a multifaceted phenomenon that can arise from genetic, epigenetic, and microenvironmental factors. Various mechanisms have been discovered and extensively studied, including drug inactivation, reduced intracellular drug accumulation by reduced uptake or increased efflux, drug target alteration, activation of compensatory pathways for cell survival, regulation of DNA repair and cell death, tumor plasticity, and the regulation from tumor microenvironments (TMEs). To overcome cancer resistance, a variety of strategies have been proposed, which are designed to enhance the effectiveness of cancer treatment or reduce drug resistance. These include identifying biomarkers that can predict drug response and resistance, identifying new targets, developing new targeted drugs, combination therapies targeting multiple signaling pathways, and modulating the TME. The present article focuses on the different mechanisms of drug resistance in cancer and the corresponding tackling approaches with recent updates. Perspectives on polytherapy targeting multiple resistance mechanisms, novel nanoparticle delivery systems, and advanced drug design tools for overcoming resistance are also reviewed.

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Effect of 5‐fluorouracil on excision repair cross‐complementing 1 expression and consequent cytotoxicity regulation in human gastric cancer cells

Cited by 10 publications

References 30 publications

MKK3 sustains cell proliferation and survival through p38DELTA MAPK activation in colorectal cancer

MKK3 sustains cell proliferation and survival through p38DELTA MAPK activation in colorectal cancer

The p38 MAPK Signaling Activation in Colorectal Cancer upon Therapeutic Treatments

Understanding and targeting resistance mechanisms in cancer

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