Secreted Pyruvate Kinase M2 Promotes Lung Cancer Metastasis through Activating the Integrin Beta1/FAK Signaling Pathway

Wang, Caihong; Zhang, Shaosen; Liu, Jie; Tian, Yue; Ma, Boyuan; Xu, Shuai; Fu, Yan; Luo, Yongzhang

doi:10.1016/j.celrep.2020.01.037

Cited by 72 publications

(58 citation statements)

References 90 publications

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“…Lewis lung carcinoma originated from a spontaneous lung adenocarcinoma of a C57BL/6 mouse 32,33 . Tail vein injection of carcinoma cells was a classical method to establish models of metastasis 34‐36 . We injected the Lewis lung carcinoma cells (LLCs) into tail veins of six C57BL/6 mice, resulting in two lung metastases and three bone metastases.…”

Section: Resultsmentioning

confidence: 99%

BMP2 signalling activation enhances bone metastases of non‐small cell lung cancer

Huang

Yun

et al. 2020

J Cellular Molecular Medi

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Distant metastases occur when non‐small cell lung cancer (NSCLC) is at late stages. Bone metastasis is one of the most frequent metastases of NSCLC and leads to poor prognosis. It has been reported that high expression of BMP2 in NSCLC correlates with poor survival, but whether BMP2 contributes to NSCLC bone metastasis remains largely unknown. The activation of BMP signalling is found in metastatic bone tumours of mice Lewis lung carcinoma and predicts poor survival in human NSCLC. BMP2 signalling activation can enhance bone metastasis of Lewis lung carcinoma. Moreover, BMP2 secreted by stroma fibroblasts can promote the migration and invasion of NSCLC cells. Besides, in combination with pre‐osteoblast and LLCs, BMP2 could enhance the differentiation of macrophages into osteoclasts to play roles in the osteolytic mechanism of NSCLC bone metastasis. Interestingly, NSCLC cells can also enrich BMP2 to pre‐osteoblasts to function in the osteoblastic mechanism. Our results firstly demonstrate the detailed mechanisms about what roles BMP2 signalling play in enhancing NSCLC bone metastases. These findings provide a new potential therapy choice for preventing bone metastases of NSCLC via the inhibition of BMP2 signalling.

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Section: Resultsmentioning

confidence: 99%

BMP2 signalling activation enhances bone metastases of non‐small cell lung cancer

Huang

Yun

et al. 2020

J Cellular Molecular Medi

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“…Further insights into the metabolic and non-metabolic roles of PKM2, and apparently discrepant functions, have been highlighted in several reports (e.g. Iqbal et al 2014;Amim et al 2019;Zahra et al 2020;Wang et al 2020a;Pascale et al 2020).…”

Section: The Warburg Effect: Essential Part Of Metabolic Reprogramminmentioning

confidence: 94%

Revisiting the Warburg effect: historical dogma versus current understanding

Vaupel

Multhoff

2021

The Journal of Physiology

522

335

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Contrary to Warburg's original thesis, accelerated aerobic glycolysis is not a primary, permanent and universal consequence of dysfunctional or impaired mitochondria compensating for poor ATP yield per mole of glucose. Instead, in most tumours the Warburg effect is an essential part of a ‘selfish’ metabolic reprogramming, which results from the interplay between (normoxic/hypoxic) hypoxia‐inducible factor‐1 (HIF‐1) overexpression, oncogene activation (cMyc, Ras), loss of function of tumour suppressors (mutant p53, mutant phosphatase and tensin homologue (PTEN), microRNAs and sirtuins with suppressor functions), activated (PI3K–Akt–mTORC1, Ras–Raf–MEK–ERK–cMyc, Jak–Stat3) or deactivated (LKB1–AMPK) signalling pathways, components of the tumour microenvironment, and HIF‐1 cooperation with epigenetic mechanisms. Molecular and functional processes of the Warburg effect include: (a) considerable acceleration of glycolytic fluxes; (b) adequate ATP generation per unit time to maintain energy homeostasis and electrochemical gradients; (c) backup and diversion of glycolytic intermediates facilitating the biosynthesis of nucleotides, non‐essential amino acids, lipids and hexosamines; (d) inhibition of pyruvate entry into mitochondria; (e) excessive formation and accumulation of lactate, which stimulates tumour growth and suppression of anti‐tumour immunity – in addition, lactate can serve as an energy source for normoxic cancer cells and drives malignant progression and resistances to conventional therapies; (f) cytosolic lactate being mainly exported through upregulated lactate–proton symporters (MCT4), working together with other H+ transporters, and carbonic anhydrases (CAII, CAIX), which hydrate CO2 from oxidative metabolism to form H+ and bicarbonate; (g) these proton export mechanisms, in concert with poor vascular drainage, being responsible for extracellular acidification, driving malignant progression and resistance to conventional therapies; (h) maintenance of the cellular redox homeostasis and low reactive oxygen species (ROS) formation; and (i) HIF‐1 overexpression, mutant p53 and mutant PTEN, which inhibit mitochondrial biogenesis and functions, negatively impacting cellular respiration rate. The glycolytic switch is an early event in oncogenesis and primarily supports cell survival. All in all, the Warburg effect, i.e. aerobic glycolysis in the presence of oxygen and – in principle – functioning mitochondria, constitutes a major driver of the cancer progression machinery, resistance to conventional therapies, and poor patient outcome. However, as evidenced during the last two decades, in a minority of tumours primary mitochondrial defects can play a key role promoting the Warburg effect and tumour progression due to mutations in some Krebs cycle enzymes and mitochondrial ROS overproduction.

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“…The expression of PKM2 was found to be enhanced in two different strains of hepatocellular carcinoma cell lines by using 2D gel electrophoresis followed by MALDI-TOF mass spectrometry (64). Immunohistological staining of blood taken from patients with colon cancer (12) and gastrointestinal (65), pancreatic, lung (66), ovarian (67), and renal cell carcinoma (RCC) (68) showed that PKM2 is released into the blood circulation. Several studies demonstrated that the expression of PKM2 is up-regulated in colorectal cancer patients (CRC) and inflammatory bowel disease and intrahepatic cholangiocarcinoma (ICC) tissues with high tumor cell necrosis, high angiogenesis, and more advanced stages.…”

Section: Pkm2 As a Diagnostic Toolmentioning

confidence: 99%

“…Additionally, some PKM2 is also released into neighboring tissues by necrosis of cancer cells and tumor cell renewal, which can be used in the early diagnosis of cancer. The PKM2 level in the circulating blood of patients may serve as a potential diagnostic marker in various carcinomas (67).…”

Section: Pkm2 As a Diagnostic Toolmentioning

confidence: 99%

Pyruvate Kinase M2 and Cancer: The Role of PKM2 in Promoting Tumorigenesis

et al. 2020

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Pyruvate kinase plays a pivotal role in regulating cell metabolism. The final and rate-limiting step of glycolysis is the conversion of Phosphoenolpyruvate (PEP) to Pyruvate, which is catalyzed by Pyruvate Kinase. There are four isomeric, tissue-specific forms of Pyruvate Kinase found in mammals: PKL, PKR, PKM1, and PKM2. PKM1 and PKM2 are formed bya single mRNA transcript of the PKM gene by alternative splicing. The oligomers of PKM2 exist in high activity tetramer and low activity dimer forms. The dimer PKM2 regulates the rate-limiting step of glycolysis that shifts the glucose metabolism from the normal respiratory chain to lactate production in tumor cells. Besides its role as a metabolic regulator, it also acts as protein kinase, which contributes to tumorigenesis. This review is focused on the metabolic role of pyruvate kinase M2 in normal cells vs. cancerous cells and its regulation at the transcriptional level. The review also highlights the role of PKM2 as a potential diagnostic marker and as a therapeutic target in cancer treatment.

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Secreted Pyruvate Kinase M2 Promotes Lung Cancer Metastasis through Activating the Integrin Beta1/FAK Signaling Pathway

Cited by 72 publications

References 90 publications

BMP2 signalling activation enhances bone metastases of non‐small cell lung cancer

BMP2 signalling activation enhances bone metastases of non‐small cell lung cancer

Revisiting the Warburg effect: historical dogma versus current understanding

Pyruvate Kinase M2 and Cancer: The Role of PKM2 in Promoting Tumorigenesis

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