The role of GLI1 for 5-Fu resistance in colorectal cancer

Zhang, Lining; Song, Ruolan; Gu, Dongsheng; Zhang, Xiaoli; Yu, Beiqin; Liu, Bingya; Xie, Jingwu

doi:10.1186/s13578-017-0145-7

Cited by 41 publications

(27 citation statements)

References 44 publications

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“…To understand the molecular basis underlying drug resistance of 5‐FU in colorectal cancer, we first generated 5‐FU resistant LoVo‐R cell line from the parental LoVo cells through gradual addition of 5‐FU for nearly a year . We compared gene expression between LoVo‐R and LoVo cells via RNA‐seq.…”

Section: Resultsmentioning

confidence: 99%

Functional significance of Hippo/YAP signaling for drug resistance in colorectal cancer

Song

Zhang

et al. 2018

Molecular Carcinogenesis

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Colorectal cancer is a leading cause of cancer-related death worldwide. While early stage colorectal cancer can be removed by surgery, patients with advanced disease are treated by chemotherapy, with 5-Fluorouracil (5-FU) as a main ingredient. However, most patients with advanced colorectal cancer eventually succumb to the disease despite some responded initially. Thus, identifying molecular mechanisms responsible for drug resistance will help design novel strategies to treat colorectal cancer. In this study, we analyzed an acquired 5-FU resistant cell line, LoVo-R, and determined that elevated expression of YAP target genes is a major alteration in the 5-FU resistant cells. Hippo/YAP signaling, a pathway essential for cell polarity, is an important regulator for tissue homeostasis, organ size, and stem cells. We demonstrated that knockdown of YAP1 sensitized LoVo-R cells to 5-FU treatment in cultured cells and in mice. The relevance of our studies to colorectal cancer patients is reflected by our discovery that high expression of YAP target genes in the tumor was associated with an increased risk of cancer relapse and poor survival in a larger cohort of colorectal cancer patients who underwent 5-FU-related chemotherapy. Taken together, we demonstrate a critical role of YAP signaling for drug resistance in colorectal cancer.

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Section: Resultsmentioning

confidence: 99%

Functional significance of Hippo/YAP signaling for drug resistance in colorectal cancer

Song

Zhang

et al. 2018

Molecular Carcinogenesis

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“…Chemotherapeutic treatment of colorectal cancer is based on 5-fluorouracil (5-FU) which is an anticancer drug interfering with nucleoside metabolism through incorporation into RNA and DNA. This leads to cell death ( 6 , 19 , 20 ). After treatment of LoVo cells without altered expression of LMNB1 with 5-FU, we observed induction of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of lamin B1 induces mitotic catastrophe in colon cancer LoVo cells and is associated with worse clinical outcomes

2017

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Lamins are the major components of the nuclear lamina and play important roles in many cellular processes. The role of lamins in cancer development and progression is still unclear but it is known that reduced expression of lamin B1 has been observed in colon cancer. Thus, the aim of the present study was to elucidate the influence of LMNB1 upregulation on colon cancer cell line after treatment with 5-FU. The results indicate, that overexpression of LMNB1 induced dose-dependent cell death mainly by mitotic catastrophe pathway. Furthermore, after upregulation of this intermediate protein, lower expression of lamin A/C was observed. Moreover, we observed an increase in fluorescence intensity of nuclear β-catenin and decrease in cell-cell interaction area, that was connected with inhibition of colon cancer cells migration. We present the reorganization of actin filament and β-tubulin, because these cytoskeletal proteins are directly or indirectly linked with lamins, and analyzing publicly available mRNA data we show that patients with overexpression of LMNB1 are characterized by lower survival rates within the first 30 months from diagnosis. Summarizing our results, upregulation of LMNB1 induce mitotic catastrophe and only small percentage of apoptosis. Moreover, we showed inhibition of cell migration and promotion of cell-cell contact as a results of direct and indirect regulation of β-catenin, lamin A/C, actin and tubulin. However, it is possible that mitotic catastrophe cells in patients with colorectal cancer may be a reservoir of the cells responsible for faster disease progression, and further investigations are necessary to confirm this hypothesis.

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“…Finally, some pathways such as Hedgehog signaling, initially described as important regulators of embryonic development, tissue polarity, and cell differentiation (EMT), were also described to be involved in CRC development and 5‐FU resistance through an increase of GLI1 expression in 5‐FU‐resistant cells. Indeed, it was observed that GLI1 knockdown sensitized CRC cells to 5‐FU treatment, reducing tumor invasiveness 31 …”

Section: Cellular Functions Disrupted By 5‐fumentioning

confidence: 99%

5‐Fluorouracil resistance mechanisms in colorectal cancer: From classical pathways to promising processes

et al. 2020

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Colorectal cancer (CRC) is a public health problem. It is the third most common cancer in the world, with nearly 1.8 million new cases diagnosed in 2018. The only curative treatment is surgery, especially for early tumor stages. When there is locoregional or distant invasion, chemotherapy can be introduced, in particular 5‐fluorouracil (5‐FU). However, the disease can become tolerant to these pharmaceutical treatments: resistance emerges, leading to early tumor recurrence. Different mechanisms can explain this 5‐FU resistance. Some are disease‐specific, whereas others, such as drug efflux, are evolutionarily conserved. These mechanisms are numerous and complex and can occur simultaneously in cells exposed to 5‐FU. In this review, we construct a global outline of different mechanisms from disruption of 5‐FU‐metabolic enzymes and classic cellular processes (apoptosis, autophagy, glucose metabolism, oxidative stress, respiration, and cell cycle perturbation) to drug transporters and epithelial‐mesenchymal transition induction. Particular interest is directed to tumor microenvironment function as well as epigenetic alterations and miRNA dysregulation, which are the more promising processes that will be the subject of much research in the future.

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The role of GLI1 for 5-Fu resistance in colorectal cancer

Cited by 41 publications

References 44 publications

Functional significance of Hippo/YAP signaling for drug resistance in colorectal cancer

Functional significance of Hippo/YAP signaling for drug resistance in colorectal cancer

Overexpression of lamin B1 induces mitotic catastrophe in colon cancer LoVo cells and is associated with worse clinical outcomes

5‐Fluorouracil resistance mechanisms in colorectal cancer: From classical pathways to promising processes

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