PKM2 upregulation promotes malignancy and indicates poor prognosis for intrahepatic cholangiocarcinoma

Qian, Ze; Hu, Wendi; Lv, Zhen; Liu, Hua; Chen, Diyu; Wang, Yacong; Wu, Jian; Zheng, Shusen

doi:10.1016/j.clinre.2019.06.008

Cited by 22 publications

(17 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additionally, high PKM2 expression was significantly associated with the M1 stage in patients with CCA. This clinical observation agrees with that in other cancer types (10,12,32). Over the past decade, the evidence has indicated that genetic alteration by activation of oncogenes, and inactivation of tumor-suppressor genes may regulate expression and functions of PKM2.…”

Section: Discussionsupporting

confidence: 89%

“…PKM2 is an enzyme that plays an important role in glycolysis and is predominantly expressed during embryonic development, in highly proliferating cells, and in cancer cells (30,31). It was recently reported that increased inflammatory signaling and PKM2 expression contribute to tumorigenesis of hilar cholangiocarcinoma induced by chronic inflammation (32). Additionally, high PKM2 expression was significantly associated with the M1 stage in patients with CCA.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Antitumor Effect of Shikonin, a PKM2 Inhibitor, in Cholangiocarcinoma Cell Lines

et al. 2020

View full text Add to dashboard Cite

Background/Aim: Pyruvate kinase M2 (PKM2) is an enzyme that is predominantly overexpressed in various types of cancer. The role of PKM2 in liver fluke-associated cholangiocarcinoma (CCA) remains unclear. This study aimed to investigate the antitumor activity of shikonin, a PKM2 inhibitor, in CCA cells. Materials and Methods: Immunohistochemistry and immunoblotting were used to determine PKM2 expression in CCA tissues and cells. Antiproliferative effects of shikonin were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, colony-formation and trypan blue exclusion assays. The antimetastatic activity of shikonin was determined using the Boyden chamber assay. Mechanisms by which shikonin inhibited CCA progression were determined. Results: PKM2 was overexpressed in CCA compared to normal bile duct epithelial cells. Shikonin significantly inhibited growth, and migration of CCA cells while inducing their death. A mechanistic study revealed that antitumor effects of shikonin in CCA cells depended on increased production of reactive oxygen species. Conclusion: Shikonin may be a novel therapeutic agent for patients with CCA. Cholangiocarcinoma (CCA) is an aggressive malignancy which originates from bile duct epithelia. The highest incidence and mortality rate of CCA was found in Southeast Asian countries, especially in northeastern Thailand (1). Recent epidemiological studies indicated that the incidence of CCA is different according to geographical risk factors and genetic backgrounds. Thamavit et al. showed that the infection with liver fluke, namely Opisthorchis viverrini (OV), is strongly associated with CCA development in Thailand, an area in which OV is endemic (2). Most patients with CCA present with an advanced stage of the disease, leading to a late diagnosis, poor prognosis and a short survival (3). Although surgical resection has remained a good choice for CCA therapy, only a very small number of cases can be operated on and this results in a high recurrence. At present, few neoadjuvant or adjuvant treatments for CCA are available as treatment options for patients with unresectable CCA or for after surgery. Chemoresistance and tumor relapse are still high in patients with CCA (4). Therefore, a new effective therapeutic agent for CCA is needed. Metabolic reprogramming, first described by Hanahan and Weinberg, is a cancer hallmark (5). Most cancer cells prefer to use aerobic glycolysis than mitochondrial metabolism; this is known as the Warburg effect. Up-regulation of glycolytic enzymes have been reported in several cancer types including CCA, suggesting that these enzymes are potential targets for diagnosis and therapy of cancer (6). Pyruvate kinase M2 (PKM2), a key enzyme in the glycolytic pathway, is an isomeric form of pyruvate kinase, occurring in four isoforms: R, L, M1, and M2. PKM2 exhibits two major states, one is a highly active state in the tetrameric form and the other is the less active state in the dimeric form (7). Dimeric PKM2 facilitates the production of glycolytic int...

show abstract

Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Antitumor Effect of Shikonin, a PKM2 Inhibitor, in Cholangiocarcinoma Cell Lines

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Recent studies have shown that the PKM2 expression was also a potential histopathological marker for the differential diagnosis of malignant and precancerous endometrial lesions, and high PKM2 expression in endometrial cancer is conducive to poor prognosis. [32][33][34] C Papadaki et al also indicated that PKM2 as a biomarker for chemosensitivity to front-line platinum-based chemotherapy in patients with metastatic non-smallcell lung cancer. 35 In this study, we explored the correlation between high PKM2 expression and clinical diagnosis.…”

Section: Discussionmentioning

confidence: 99%

Elevating PKM2 Expression Indicates a Biomarker of Poor Prognosis in Patients With Liver Cancer

Zhang

et al. 2021

Preprint

View full text Add to dashboard Cite

M2 isoform of pyruvate kinase (PKM2) plays an important role in reprogramming of cell metabolism which is a hall-marker of tumorigenesis. PKM2 expression altering is closely related to cancer metabolism and tumor growth. In the present study, we analyzed the role of PKM2 expression in liver cancer in order to clarify its potential application value in the diagnosis and prognosis of liver cancer patients. In cancerous liver tissues, the PKM2 expression was significantly higher than normal tissues. High PKM2 expressing was related to patient’s age, gender, histological type, grade, stage, T classification and poor survival. Patients with Higher PKM2 expression had a shorter OS (P = 0.0013) and RFS (P = 0.027). ROC and Multivariate Cox analysis showed that high PKM2expression was a risk factor for patients’ poor prognosis. GSEA identified mitotic spindle, PI3K/Akt/mTOR signaling, notch signaling, apoptosis, G2M checkpoint and Wnt/β- Cantenin signaling were enriched with high PKM2 expression phenotype. These findings suggested PKM2 expression has potential as a predictive biomarker for the diagnosis and prognosis of patients with liver cancer.

show abstract

“…Staining for PKM2 was scored based on a 12-point semi-quantitative scoring system [12] . The positivity of the reaction was scored by counting the number of positive cells: 0%-25% (1), 26%-50% (2), 51%-75% (3), and 75% (4).…”

Section: Scoring Of Pkm2 Expressionmentioning

confidence: 99%

“…The advantage of the low active dimeric form promotes the accumulation of phosphometabolites, enabling tumor cells to participate in high levels of synthetic processing to meet their energy and material needs [11] . In addition, PKM2 can regulate the key signaling pathways to control cell diverse biological functions as a transcriptional coactivator [12] . Therefore, PKM2 is currently believed to play an important role in tumor metabolism and progression.…”

Section: Introductionmentioning

confidence: 99%

Pyruvate Kinase M2 is Highly Expressed in Cutaneous Squamous Cell Carcinoma and Promotes its Progression

Liu

Shi

Zhang

et al. 2021

Preprint

View full text Add to dashboard Cite

Background: Pyruvate kinase M2 (PKM2) is conducive to tumor formation and progression for several types of cancer. Its role in the tumorigenesis and progress of cutaneous squamous cell carcinoma (CSCC) remains unknown. We sought to explore the expression and function of PKM2 in CSCC.Methods: The expression of PKM2 in 62 cases of actinic keratoses (AK), 15 cases ofBowen´s diseases (BD), 66 cases of CSCC and 10 cases of normal skin tissues (NT) were detected by immunohistochemistry. The staining patterns were assessed using a 12-point semi-quantitative scoring system. Immunohistology scores were statistically analysed. We further established a stable PKM2 knockdown CSCC cell line to explore its effect on cell biological behaviors. In this study, we used western blotting, CCK-8 assay, colony formation test, transwell assay, wound-healing assay, glucose concentration assay and lactate concentration assay.Results: We found that the expression of PKM2 increased significantly in AK, BD and CSCC, compared to that in NT. In addition, a comparison of PKM2 expression percentage showed that there was significantly difference among these three diseases. Then, we observed that PKM2 expression was associated with infiltration depth in 62 AK patient and course of disease in 15 BD patients. Moreover, high expression of PKM2 in 66 CSCC patients was significantly related with position, histological grade and Broder stage. In addition, PKM2 knockdown could obviously inhibit CSCC cell proliferation, invasion, migration and aerobic glycolysis in vitro. Finally, the expression levels of the phosphorylated- (p-) p38 of the MAPK pathway in the PKM2 knockdown groups greatly decreased compared with those of the controls in CSCC cell lines.Conclusions: PKM2 is differently expressed in CSCC-related diseases. PKM2 is highly expressed in CSCC and promotes its progression, which may be associated with the activation of p38 MARK signaling pathway. PKM2 may be a potential therapeutic target for CSCC.

show abstract

PKM2 upregulation promotes malignancy and indicates poor prognosis for intrahepatic cholangiocarcinoma

Cited by 22 publications

References 34 publications

Antitumor Effect of Shikonin, a PKM2 Inhibitor, in Cholangiocarcinoma Cell Lines

Antitumor Effect of Shikonin, a PKM2 Inhibitor, in Cholangiocarcinoma Cell Lines

Elevating PKM2 Expression Indicates a Biomarker of Poor Prognosis in Patients With Liver Cancer

Pyruvate Kinase M2 is Highly Expressed in Cutaneous Squamous Cell Carcinoma and Promotes its Progression

Contact Info

Product

Resources

About