Pyruvate kinase M2 fuels multiple aspects of cancer cells: from cellular metabolism, transcriptional regulation to extracellular signaling
© The Author(s). 2018
Received: 11 October 2017
Accepted: 1 February 2018
Published: 19 February 2018
Originally identified as a metabolic enzyme that catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to ADP in the glycolytic pathway, pyruvate kinase M2-type (PKM2) has been shown to exhibit novel biological activities in the nucleus and outside the cells. Although cell-based studies reveal new non-canonical functions of PKM2 in gene transcription, epigenetic modulation and cell cycle progression, the importance of these non-canonical functions in PKM2-mediated tumorigenesis is still under debate because studies in genetically modified mice do not consistently echo the findings observed in cultured cancer cells. In addition to regulation of gene expression, the existence of PKM2 in exosomes opens a new venue to study the potential role of this glycolytic enzyme in cell-cell communication and extracellular signal initiation. In this review, we briefly summarize current understanding of PKM2 in metabolic switch and gene regulation. We will then emphasize recent progress of PKM2 in extracellular signaling and tumor microenvironment reprogramming. Finally, the discrepancy of some PKM2’s functions in vitro and in vivo, and the application of PKM2 in cancer detection and treatment will be discussed.
Biochemical analysis by charactering the enzymatic activity that catalyzes the formation of lactate from glucose in cell lysates revealed the first intracellular metabolic pathway, the glycolytic pathway. Beginning from the purification of fractions that contained glycolytic activity, a number of pioneer researchers contributed to the identification of enzymes that involve in each step in the pathway [1–3]. These results build up our modern concept in the interchange of aerobic and anaerobic respiration and energy production under various physiological and pathological circumstances.
The existence of an enzyme that catalyzed the production of ATP by transferring a phosphate group from PEP to ADP in the liver was first reported in 1934 . Subsequent isolation of the enzyme, known as pyruvate kinase (PK) later, demonstrated differences in tissue distribution and catalytic kinetics suggesting this enzyme may have different isoforms [5–8]. During 1982 to 1984, various PK genes were cloned from yeast, chicken and rat [9–12]. The functional study of PKM2 was initiated by the identification of a candidate gene in mouse in early 1980s . Later, Noguchi et al. showed that two isoforms of PK (PKM1 and PKM2) are encoded by the same PKM gene via alternative splicing . In human, PKM isoforms are also produced via a similar splicing mechanism by including exon 9 and 10 into PKM1 and PKM2 mRNA separately .
Several findings caught researcher’s attention to the potential role of PKM2 in tumorigenesis. First, PKM2 is the embryonic isoform that highly expressed during animal development. Its transcription is attenuated in a number of adult tissues while it is reactivated in tumors [14, 15]. Second, study of the relative abundance of PKM1 and PKM2 in normal and tumor tissues demonstrated a switch from the PKM1 isoform to the PKM2 isoform in various cancers like hepatocellular carcinoma [16, 17]. Third, the change of mRNA splicing from PKM1 to PKM2 is enhanced by c-Myc oncogene suggesting cancer cells actively engage in this switch to fit their requirement in proliferation and metabolism . Fourth, modulation of PKM2 activity by activators or inhibitors affect tumor growth in vivo [19–21].
The first episode: PKM2 as a metabolic enzyme in the cytoplasm
The second episode: PKM2 as a signaling modulator in the cytoplasm
In addition to function as a glycolytic enzyme, PKM2 is proposed to involve in more cellular processes due to the identification of interacting proteins in the cytoplasm. For example, PKM2 was shown to be an interacting protein of several tyrosine kinases including A-Raf, Break point cluster region-Abelson (BCR-ABL) fusion kinase, fibroblast growth factor receptor 1 (FGFR1) etc. [32, 33]. These binding partners have been shown to modulate the dimeric/tetrameric change of PKM2 to alter cell metabolism. However, it is possible that PKM2 may reciprocally affect the catalytic kinetics, substrate binding and cytoplasmic location of these binding partners to modulate signal transduction. The finding that PKM2 is a phosphor-tyrosine binding protein strengthens this possibility because many intracellular signaling mediators can bind to phosphor-tyrosine residue to assemble specific protein complexes for signal transmission . To date, the list of PKM2 binding partners grows continuously. We highlight several new members and discuss their biological implication here. Mukheriee et al. demonstrated that PKM2 could bind with HuR, a RNA binding protein which plays an important role in the control of mRNA stability and translational efficiency, to promote cell cycle progression and proliferation of glioma cells . Interestingly, another RNA binding protein tristetraprolin which could bind a number of mRNA via the AU-rich element at 3′-untranslational region (3’-UTR) was also found to be a PKM2 interacting partner, and PKM2 induced phosphorylation and degradation of tristetraprolin to modulate breast cancer growth . These two studies imply a potential translational control function of PKM2. Recently, Liang et al. identified the anti-apoptotic protein Bcl2 as a new PKM2 partner . They demonstrated that oxidative stress induced the translocation of PKM2 into mitochondria where it phosphorylated and stabilized Bcl2 by preventing its degradation via ubiquitination-dependent pathway. These data suggested that PKM2 helps cancer cells to adapt oxidative stress elicited by intracellular metabolic change or extracellular insult.
The third episode: PKM2 as a transcriptional regulator in the nucleus
A nuclear role of PKM2 in the regulation of gene transcription or epigenetic modification was firstly suggested by the finding that PKM2 bound with Y333-phosphorlated β-catenin, and the β-catenin-PKM2 complex was recruited to the nucleosomes to phosphorylate histone H3 at threonine 11  (Fig. 1). This phosphorylation subsequently increased histone H3 acetylation that led to upregulation of β-catenin target genes. Another transcription factor directly phosphorylated by PKM2 is signal transducer and activator of transcription 3 (STAT3) . PKM2-mediated phosphorylation of STAT3 at tyrosine 705 enhanced STAT3 activity to upregulate the expression of mitogen-activated protein kinase kinase 5 (MEK5). Beside transcription factors, PKM2 has been shown to phosphorylate myosin light chain 2 (MLC2), BUB3 and extracellular signal-regulated kinase 1 and 2 (ERK1 and ERK2) [40–42]. Interestingly, PKM2 also acts via phosphorylation-independent manner to affect gene expression. For example, PKM2 has been found to bind with Oct4, one of the master transcription factors that control self-renewal of stem cells, and inhibit Oct4-mediated transcription . PKM2 can also enhance tumor angiogenesis by interacting with NF-κB and HIF-1α in the nucleus and activating the expression of HIF-1α target gene VEGF-A. Consequently, increased secretion of VEGF-A boosts blood vessel formation which contributes to tumor growth . Although these studies strongly suggested the nuclear localization and protein kinase function of PKM2 in various physiological and pathological circumstances, however the importance of nuclear PKM2-mediated gene expression has been challenged by studies using PKM2 knockout cells. By using [32P]-labeled PEP and PKM2-null mouse embryonic fibroblasts, Hosios et al. showed that PEP-dependent phosphorylation is not a common event in cells and the reaction is not catalyzed by PKM2 . The discrepancy of these studies is currently unresolved and the protein kinase activity of PKM2 needs further confirmation.
The fourth episode: PKM2 as an extracellular signaling communicator
The presence of extracellular PKM2 opens a new avenue for the study of PKM2 biological function. Buschow et al. provided the first evidence that PKM2 could be detected in B-cell exosomes and was identified as a MHC class II-associated protein . Two subsequent studies also indicated that PKM2 is existed in exosomes released by various cells [47, 48]. Currently, several public databases like ExoCarta and EVpedia provide comprehensive information for the components including proteins, lipids, nucleic acids of extracellular vesicles in different species. All of the data confirm that PKM2 is a package protein of exosomes. Recent studies have clearly demonstrated a communicative role of exosomes by delivering different components from host cells to recipient cells [49–51]. It is expectable that PKM2 may play a role in cell-cell crosstalk.
Emerging evidence indeed support this hypothesis. For example, a recent study demonstrated that blood circulating PKM2 may promote tumor growth and angiogenesis by increasing the growth, migration and matrix adhesion of endothelial cells . Another investigation also showed that PKM2 secreted from colon cancer cells might act via an autocrine stimulation to enhance cell migration by activating the PI3K/Akt and Wnt/β-catenin pathways . In addition to cancer cells, neutrophils at the tissues damage sites could release PKM2 to promote angiogenesis and wound healing . Our recent study also demonstrated that recombinant PKM2 protein could induce phosphorylation and activation of epidermal growth factor receptor (EGFR) . Moreover, we found that R339E mutant PKM2 which preferentially formed dimeric PKM2 activated EGFR more significantly than the tetrameric PKM2. Keller et al. identified 154 proteins as potential substrates for PKM2 after treatment of Hela cells with succinyl-5-aminoimidazole-4-carboxamide-1-ribose-5′-phosphate (SAICAR), an intracellular metabolite which could stimulate the protein kinase activity of PKM2 . They also found EGFR as a PKM2 substrate. Their results are different from ours in two ways. First, the signaling pathways activated in our study are elicited by extracellular PKM2 while the molecular targets identified in their study are potential substrates of intracellular PKM2. Second, increase of ERK1/2 activity in our study is initiated by EGFR activation while ERK1/2 activation in their study is directly stimulated by the SAICAR/PKM2 complex. One similar phenomenon observed in both studies is that R339E mutant PKM2 activates signaling molecules more significantly than the wild type PKM2 suggesting the distinct role of dimeric and tetrameric PKM2 in oncogenesis. By using receptor tyrosine kinase array, we found that extracellular PKM2 only activated limited growth factor receptors in breast cancer cells (data not shown). Currently, the selectivity of receptor activation by extracellular PKM2 remains unknown. In addition, why R339E mutant PKM2 is more potent in the activation of EGFR is also not clear. More experiments are needed to answer these questions.
The fifth episode: unanswered discrepancy of PKM2
In addition to the cell-based data discussed above, the oncogenic role of PKM2 has also been challenged after the generation of PKM2 knockout mice. Israelsen et al. generated a conditional knockout mouse model by deleting the PKM2-specific exon 10 . Surprisingly, depletion of PKM2 accelerated but not attenuated tumor formation driven by loss of Brca1 gene in mice. These data indicated that PKM2 is not required for the proliferation of cancer cells. Interestingly, PKM1 expression was only detected in non-proliferating tumor cells suggesting a tumor-suppressive role of PKM1 in breast cancer. In addition, PKM2 knockout mice have a high incidence to develop hepatocellular carcinoma spontaneously after a long latency due to the imbalance in metabolism . These results against the notion that PKM2 plays an oncogenic role in vivo.
The continuing episode: is PKM2 a cancer biomarker and drug target?
Prognostic significance of PKM2 in human cancers
PKM2, ENO1, gp96
PKM2, ACVR 1C
PKM2, GAPDH, ATP5B
PKM2, HK1, PFKB
On the contrary, the use of PKM2 as a diagnostic factor is controversial. A proteomic analysis demonstrated that PKM2 is a potential diagnostic marker for the detection of lung cancer . However, a recent study suggested PKM2 is not a good diagnostic marker for lung cancer due to low specificity . Similarly, PKM2 alone is unlikely to be a useful marker for the screening of colon cancer . However, combination of multiple markers could increase sensitivity and specificity for cancer diagnosis .
The therapeutic potential of PKM2 is an intriguing event in cancer treatment. From one side, inhibition of PKM2 is expected to inhibit glycolysis, impair gene transcription and suppress cellular proliferation. Therefore, PKM2 inhibitors seem to be good candidates for anti-cancer drug development. By using library screening, Vander Heiden et al. identified three novel classes of PKM2 inhibitors and showed that the most effective compound inhibited PKM2 activity and induced death of cancer cells . Recently, Ning et al. found that novel naphthoquinone derivatives are potent PKM2 inhibitors . One effective compound 3 k suppressed the proliferation of multiple cancer cell lines at sub-micromolar concentrations while it showed little detrimental effect on normal cells. From the other side, activation of PKM2 may also inhibit tumor growth. Because the low activity PKM2 dimer is the major isoform that triggers glycolysis in the cytoplasm and gene transcription in the nucleus in cancer cells, PKM2 activators which can promote the formation of tetrameric PKM2 may switch glycolysis to mitochondria pathway and reduce nuclear entry to attenuate gene transcription. Both effects impair metabolic demand and growth-supporting signaling that leads to tumor regression. Two pioneer studies identified various PKM2 activators and characterized their specificity in vitro [88, 89]. A subsequent study demonstrated that PKM2 activators indeed promoted tetramer formation and suppressed tumor growth in vivo . These results suggested PKM2 activators could be promising anti-cancer drugs.
Our understanding of PKM2 function expands dramatically in the past two decades. Originally identified as a metabolic enzyme in glycolysis, PKM2 is now found to be a multi-face protein that fuels different aspects of cancer cells to sustain tumor growth. The use of PKM2 as a prognostic marker has been validated in a variety of cancers. In addition, the application of PKM2 activators or inhibitors in cancer therapy can be expected in the coming decade.
This study was supported by the grant: CA-106-PP-15 and CA-107-PP-14 from the Ministry of Health and Welfare, Taiwan, Republic of China.
MCH and WCH wrote the manuscript. Both authors read and approved the final manuscript.
The authors declare that they have no competing interests.
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