Nuclear PKM2 contributes to gefitinib resistance via upregulation of STAT3 activation in colorectal cancer

Li, Qiong; Zhang, Daoxiang; Chen, Xiaoying; He, Lei; Li, Tianming; Xu, Xiaoping; Li, Min

doi:10.1038/srep16082

Cited by 86 publications

(94 citation statements)

References 31 publications

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“…PKM2 is upregulated in CRC providing tumor growth advantages [28, 29] contributing to gefitinib resistance via upregulation of STAT3 activation in colorectal cancer [30]. Therefore, PKM2 can be considered as a potential therapeutic target in colon and pancratic neoplasias.…”

Section: Resultsmentioning

confidence: 99%

Vitamin C uncouples the Warburg metabolic switch in KRAS mutant colon cancer

et al. 2016

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KRAS mutation is often present in many hard-to-treat tumors such as colon and pancreatic cancer and it is tightly linked to serious alterations in the normal cell metabolism and clinical resistance to chemotherapy.In 1931, the winner of the Nobel Prize in Medicine, Otto Warburg, stated that cancer was primarily caused by altered metabolism interfering with energy processing in the normal cell. Increased cell glycolytic rates even in the presence of oxygen is fully recognized as a hallmark in cancer and known as the Warburg effect.In the late 1970′s, Linus Pauling and Ewan Cameron reported that vitamin C may have positive effects in cancer treatment, although deep mechanistic knowledge about this activity is still scarce.We describe a novel antitumoral mechanism of vitamin C in KRAS mutant colorectal cancer that involves the Warburg metabolic disruption through downregulation of key metabolic checkpoints in KRAS mutant cancer cells and tumors without killing human immortalized colonocytes.Vitamin C induces RAS detachment from the cell membrane inhibiting ERK 1/2 and PKM2 phosphorylation. As a consequence of this activity, strong downregulation of the glucose transporter (GLUT-1) and pyruvate kinase M2 (PKM2)-PTB dependent protein expression are observed causing a major blockage of the Warburg effect and therefore energetic stress.We propose a combination of conventional chemotherapy with metabolic strategies, including vitamin C and/or other molecules targeting pivotal key players involved in the Warburg effect which may constitute a new horizon in anti-cancer therapies.

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Section: Resultsmentioning

confidence: 99%

Vitamin C uncouples the Warburg metabolic switch in KRAS mutant colon cancer

et al. 2016

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“…STAT3 activation could regulate mesenchymal stem cells (MSCs)‐induced chemo‐resistance in osteosarcoma cell (Tu et al, ). Activation of STAT3 by nuclear PKM2 has been shown to be associated with gefitinib resistance in colorectal cancer cells (Li et al, ). However, in our study, STAT3 was also activated by TKIs in EGFR‐TKI‐sensitive NSCLC cell‐lines.…”

Section: Discussionmentioning

confidence: 99%

Tyrosine kinase inhibitor‐induced IL‐6/STAT3 activation decreases sensitivity of EGFR‐mutant non‐small cell lung cancer to icotinib

Wang

Zheng

et al. 2018

Cell Biology International

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Tyrosine kinase Inhibitors (TKIs) of epidermal growth factor receptor (EGFR) has considerably benefited for non-small cell lung carcinomas (NSCLC) harbor mutations in EGFR. However, the factors attenuating EGFR-TKI efficiency are obstacles to inhibit the proliferation of EGFR-mutant NSCLC cells successfully. Clarifying the insensitivity mechanisms of EGFR-TKI would help to develop new treatment strategy. In this study, the sensitivity of EGFR-mutant NSCLC cell lines, PC9 and HCC827, to icotinib was detected. Similar with other EGFR-TKIs such as gefitinib and erlortinib in previous research, the proliferation of two cell lines was apparently inhibited. However, we surprisingly found that contrast with the suppression of EGFR-AKT/ERK pathway, STAT3 was significantly activated in PC9 cells with the treatment of icotinib, but not in HCC827 cells. Further study confirmed that icotinib concomitantly induced IL-6 secretion and src activation in PC9 cells. Moreover, with the treatment of IL-6 neutralizing antibody or src inhibitor, dasatinib, icotinib-induced phosphorylation of STAT3 was reduced, as well as the sensitivity of PC9 to icotinib was also partially increased. Our results suggest that Src/IL-6/STAT3 bypass pathway is activated to maintain cell survival when the EGFR pathway was inhibited by TKIs, even in some EGFR-mutant NSCLC cells sensitive to TKIs. This finding provides a groundwork for potential combinatorial treatment with TKIs and Src or STAT3 inhibitor to improve icotinib sensitivity.

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“…These glycolytic enzymes have acquired additional non-glycolytic functions in many aspects. For example, pyruvate kinase M2 (PKM2) facilitates colon cancer cell migration and drug resistance via the modulation of STAT3 signal [13,14]. Alpha-enolase (ENO1) promotes cell glycolysis, growth, migration, and invasion in non-small cell lung cancer through FAK-mediated PI3K/AKT pathway [15], and ENO1 is confirmed as a novel substrate of FBXW7 in colorectal cancer [16].…”

Section: Discussionmentioning

confidence: 99%

Aldolase B Overexpression is Associated with Poor Prognosis and Promotes Tumor Progression by Epithelial-Mesenchymal Transition in Colorectal Adenocarcinoma

Li¹,

Li²,

et al. 2017

Cell Physiol Biochem

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Background: Glycolysis is considered to be the root of cancer development and progression, which involved a multi-step enzymatic reaction. Our study aimed at figuring out which glycolysis enzyme participates in the development of colorectal cancer and its possible mechanisms. Methods: We firstly screened out Aldolase B (ALDOB) by performing qRT-PCR arrays of glycolysis-related genes in five paired liver metastasis and primary colorectal tissues, and further detected ALDOB protein with immunohistochemistry in tissue microarray (TMA) consisting of 229 samples from stage I-III colorectal cancer patients. CRISPR-Cas9 method was adopted to create knock out colon cancer cell lines (LoVo and SW480) of ALDOB. The effect of ALDOB on cell proliferation and metastasis was examined in vitro using colony formation assay as well as transwell migration and invasion assay, respectively. Results: In TMA, there was 64.6% of samples demonstrated strong intensity of ALDOB. High ALDOB expression were associated with poor overall survival and disease-free survival in both univariate and multivariate regression analyses (P<0.05). In vitro functional studies of CCK-8 demonstrated that silencing ALDOB expression significantly (P<0.05) inhibited proliferation, migration and invasion of colon cancer cells. Mechanically, silencing ALDOB activated epithelial markers and repressed mesenchymal markers, indicating inactivation of ALDOB may lead to inhibition of epithelial-mesenchymal transition (EMT). Conclusion: Upregulation of ALDOB promotes colorectal cancer metastasis by facilitating EMT and acts as a potential prognostic factor and therapeutic target in colorectal cancer.Q. Li and Y. Li contributed equally to this work.

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Nuclear PKM2 contributes to gefitinib resistance via upregulation of STAT3 activation in colorectal cancer

Cited by 86 publications

References 31 publications

Vitamin C uncouples the Warburg metabolic switch in KRAS mutant colon cancer

Vitamin C uncouples the Warburg metabolic switch in KRAS mutant colon cancer

Tyrosine kinase inhibitor‐induced IL‐6/STAT3 activation decreases sensitivity of EGFR‐mutant non‐small cell lung cancer to icotinib

Aldolase B Overexpression is Associated with Poor Prognosis and Promotes Tumor Progression by Epithelial-Mesenchymal Transition in Colorectal Adenocarcinoma

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