Overexpression of pyruvate kinase M2 associates with aggressive clinicopathological features and unfavorable prognosis in oral squamous cell carcinoma

Wang, Yanling; Zhang, Xiaomin; Zhang, Yuchao; Zhu, Yuming; Yuan, Chunping; Qi, Bin; Zhang, Wei; Wang, Dongmiao; Ding, Xu; Wu, Heming; Cheng, Jie

doi:10.1080/15384047.2015.1030551

Cited by 35 publications

(26 citation statements)

References 28 publications

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“…Our results demonstrate that both PKM2 or LDHA are significant prognostic markers in pancreatic cancer and the combination provides improved stratification of outcome. These results are in line with previous publications showing a significant prognostic effect of LDHA or PKM2 in other tumour types, including squamous cell carcinoma, cholangiocarcinoma and gastric cancer [ 43 , 54 , 55 ]. The exact mechanisms associated with the overexpression of PKM2 and LDHA that lead to poor prognosis remain unclear.…”

Section: Discussionsupporting

confidence: 93%

Pyruvate Kinase M2 and Lactate Dehydrogenase A Are Overexpressed in Pancreatic Cancer and Correlate with Poor Outcome

et al. 2016

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Pancreatic cancer has a 5-year survival rate of less than 4%. Despite advances in diagnostic technology, pancreatic cancer continues to be diagnosed at a late and incurable stage. Accurate biomarkers for early diagnosis and to predict treatment response are urgently needed. Since alteration of glucose metabolism is one of the hallmarks of cancer cells, we proposed that pyruvate kinase type M2 (M2PK) and lactate dehydrogenase A (LDHA) enzymes could represent novel diagnostic markers and potential therapeutic targets in pancreatic cancer. In 266 tissue sections from normal pancreas, pancreatic cystic neoplasms, pancreatic intraepithelial neoplasia (PanIN) and cancer, we evaluated the expression of PKM2, LDHA, Ki-67 and CD8+ by immunohistochemistry and correlated these markers with clinicopathological characteristics and patient survival. PKM2 and LDHA expression was also assessed by Western blot in 10 human pancreatic cancer cell lines. PKM2 expression increased progressively from cyst through PanIN to cancer, whereas LDHA was overexpressed throughout the carcinogenic process. All but one cell line showed high expression of both proteins. Patients with strong PKM2 and LDHA expression had significantly worse survival than those with weak PKM2 and/or LDHA expression (7.0 months vs. 27.9 months, respectively, p = 0.003, log rank test). The expression of both PKM2 and LDHA correlated directly with Ki-67 expression, and inversely with intratumoral CD8+ cell count. PKM2 was significantly overexpressed in poorly differentiated tumours and both PKM2 and LDHA were overexpressed in larger tumours. Multivariable analysis showed that combined expression of PKM2 and LDHA was an independent poor prognostic marker for survival. In conclusion, our results demonstrate a high expression pattern of two major glycolytic enzymes during pancreatic carcinogenesis, with increased expression in aggressive tumours and a significant adverse effect on survival.

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Section: Discussionsupporting

confidence: 93%

Pyruvate Kinase M2 and Lactate Dehydrogenase A Are Overexpressed in Pancreatic Cancer and Correlate with Poor Outcome

et al. 2016

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“…Pyruvate kinase M2 (PKM2) is a predominant mediator of cancer aerobic glycolysis, and its overexpression has been observed in multiple human cancers including OSCC . As shown in fig.…”

Section: Resultsmentioning

confidence: 99%

A 5′ AMP‐Activated Protein Kinase Enzyme Activator, Compound 59, Induces Autophagy and Apoptosis in Human Oral Squamous Cell Carcinoma

Weng

Dokla

et al. 2018

Basic Clin Pharma Tox

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5' AMP-activated protein kinase enzyme (AMPK), a master regulator of cellular metabolism, is recognized for its association with various metabolic diseases, inflammation and cancer. In this study, we aimed to investigate the role of compound 59, an AMPK activator, in a panel of oral squamous cell carcinoma (OSCC) cell lines. The antiproliferative effects of compound 59 were assessed by MTT assays, flow cytometry, Western blotting, confocal microscopy and transmission electron microscopy. Relative to OSCC cells, normal human oral keratinocytes were almost insensitive to compound 59 treatment. Compound 59 induced apoptosis as indicated by caspase activation and PARP cleavage. In addition, it inhibited JAK/STAT3 signalling, arrested cells in the G1 phase, increased reactive oxygen species (ROS) generation and promoted autophagy. Interestingly, pre-treatment with a protein tyrosine phosphatase (PP2A) inhibitor, cantharidin, partially reversed compound 59-induced down-regulation of p-JAK2 and p-STAT3, thereby suggesting the involvement of a protein tyrosine phosphatase. Together, these findings substantiate the potential of compound 59 for the treatment of OSCC patients.

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“…The oncological roles of differentially spliced transcripts of PKM including PKM1 and PKM2, which are mutually exclusive exons 9 and 10 4 , have been previously investigated. It has been reported that overexpression of PKM1/2 isoforms promotes tumorigenesis or induces poor prognoses of patients in multiple cancers 5-17 whereas PKM1 expression in place of PKM2 inhibits tumor cell proliferation 18,19 . Moreover, it has been reported that methylation or deletion of PKM2 promotes tumor progression in liver cancer, breast cancer and medulloblastoma 20-23 .…”

Section: Introductionmentioning

confidence: 99%

Discovery of functional alternatively splicedPKMtranscripts in human cancers

Zhang

Kim

et al. 2019

Preprint

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35The association of pyruvate kinase muscle type (PKM) with survival of cancer patients 36 is controversial. Here, we focus on different transcripts of PKM and investigate the 37 association between their mRNA expression and the clinical survival of the patients in 38 25 different cancers. We find that the transcript encoding PKM2, and three other 39 functional transcripts are prognostic in multiple cancers. Our integrative analysis shows 40 that the functions of these four transcripts are highly conservative in different cancers. 41Next, we validate the prognostic effect of these transcripts in an independent kidney 42 renal clear-cell carcinoma (KIRC) cohort and identify a prognostic signature which 43 could distinguish high-and low-risk KIRC patients. Finally, we reveal the functional role 44 of alternatively spliced PKM transcripts in KIRC, and discover the protein products of 45 different transcripts of PKM. Our analysis demonstrated that alternatively spliced 46 transcripts of not only PKM but also other genes should be considered in cancer 47 studies, since it may enable the discovery and targeting of the right protein product for 48 development of the efficient treatment strategies. 49 50

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Overexpression of pyruvate kinase M2 associates with aggressive clinicopathological features and unfavorable prognosis in oral squamous cell carcinoma

Cited by 35 publications

References 28 publications

Pyruvate Kinase M2 and Lactate Dehydrogenase A Are Overexpressed in Pancreatic Cancer and Correlate with Poor Outcome

Pyruvate Kinase M2 and Lactate Dehydrogenase A Are Overexpressed in Pancreatic Cancer and Correlate with Poor Outcome

A 5′ AMP‐Activated Protein Kinase Enzyme Activator, Compound 59, Induces Autophagy and Apoptosis in Human Oral Squamous Cell Carcinoma

Discovery of functional alternatively splicedPKMtranscripts in human cancers

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