The role of pyruvate kinase M2 in anticancer therapeutic treatments (Review)

Su, Qiongli; Luo, Shengping; Tan, Qiuhong; Deng, Jun; Zhou, Sichun; Peng, Mei; Tao, Ting; Yang, Xiaoping

doi:10.3892/ol.2019.10948

Cited by 29 publications

(38 citation statements)

References 101 publications

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“…Up-regulation of PKM2 is a hallmark of numerous tumor types, making it a potential therapeutic target [ 87 ]. Targeting PKM2 with some small molecules has been used in the preclinical studies to interfere with tumor growth.…”

Section: Pkm2 As a Therapeutic Targetmentioning

confidence: 99%

Protein kinase function of pyruvate kinase M2 and cancer

Chen

2020

Cancer Cell Int

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Pyruvate kinase is a terminal enzyme in the glycolytic pathway, where it catalyzes the conversion of phosphoenolpyruvate to pyruvate and production of ATP via substrate level phosphorylation. PKM2 is one of four isoforms of pyruvate kinase and is widely expressed in many types of tumors and associated with tumorigenesis. In addition to pyruvate kinase activity involving the metabolic pathway, increasing evidence demonstrates that PKM2 exerts a non-metabolic function in cancers. PKM2 has been shown to be translocated into nucleus, where it serves as a protein kinase to phosphorylate various protein targets and contribute to multiple physiopathological processes. We discuss the nuclear localization of PKM2, its protein kinase function and association with cancers, and regulation of PKM2 activity.

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Section: Pkm2 As a Therapeutic Targetmentioning

confidence: 99%

Protein kinase function of pyruvate kinase M2 and cancer

Chen

2020

Cancer Cell Int

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“…Given that PKM2 overexpression is highly associated with advanced ovarian cancers, the development of novel anticancer drugs or therapeutics that can target PKM2 could be an important strategy to improve the survival rate of patients with PKM2-overexpressing ovarian cancer. To date, several PKM2 inhibitors, including shikonin, metformin, vitamin K, and temozolomide, have been identified [10]. Our study focused on the effects of compound 3K, a specific PKM2 inhibitor, in ovarian cancer cells, and we mechanistically demonstrated that the effects of compound 3K were mediated by the targeting of metabolism for therapeutic benefit.…”

Section: Discussionmentioning

confidence: 92%

“…It has been demonstrated that autophagy is impaired by the activation of the Akt/mTOR pathway in ovarian cancer cells. Therefore, autophagy is heavily regulated by the kinase mTOR [10].…”

Section: Introductionmentioning

confidence: 99%

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Compound 3K, a Specific Pyruvate Kinase M2 Inhibitor, Induces Autophagic Cell Death through the Disruption of the Glycolytic Pathway in Ovarian Cancer Cells

Park¹,

Kundu²,

Kim³

et al. 2020

Preprint

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Ovarian cancer is the common cause of death among gynecological cancers. Although ovarian cancer initially responds to chemotherapy, the frequent recurrence in patients remains a therapeutic challenge. Pyruvate kinase M2 (PKM2) plays a pivotal role in regulating cancer cell survival. However, its therapeutic roles remain unclear. Here, we investigated the anticancer effects of compound 3K, a specific PKM2 inhibitor, on autophagic and apoptotic pathway regulation in SK-OV-3 (PKM2-overexpressing human ovarian adenocarcinoma cell line). The anticancer effect of compound 3K was examined using the MTT and colony formation assay in SK-OV-3. The results of tissue microarray showed that PKM2 expression positively correlated with the severity of the tumor. Moreover, the expression of pro-apoptotic proteins increased in SK-OV-3 following compound 3K treatment. Compound 3K induced AMPK activation, which was accompanied by the inhibition of mTOR. Additionally, this compound inhibited glycolysis, resulting in reduced proliferation in SK-OV-3. Compound 3K treatment suppressed tumor progression in vivo xenograft model. Our findings suggest that the inhibition of PKM2 by compound 3K affected Warburg effects and induced autophagic cell death. Therefore, the use of specific PKM2 inhibitors to block the glycolytic pathway and target cancer cell metabolism represents a promising therapeutic approach for treating PKM2-overexpressing ovarian cancer.

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“…However, its toxicity and poor solubility limit its application. 211 Recent studies have found that metformin can also induce tumor cell death and increase sensitivity to chemotherapy drugs by inhibiting PKM2 in osteosarcoma. 212 LDHA is located at the bifurcation point of glycolysis and oxidative phosphorylation.…”

Section: Treatments For Aerobic Glycolysismentioning

confidence: 99%

<p>Glucometabolic Reprogramming in the Hepatocellular Carcinoma Microenvironment: Cause and Effect</p>

Tian

Zhu

et al. 2020

CMAR

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Hepatocellular carcinoma (HCC) is a tumor that exhibits glucometabolic reprogramming, with a high incidence and poor prognosis. Usually, HCC is not discovered until an advanced stage. Sorafenib is almost the only drug that is effective at treating advanced HCC, and promising metabolism-related therapeutic targets of HCC are urgently needed. The "Warburg effect" illustrates that tumor cells tend to choose aerobic glycolysis over oxidative phosphorylation (OXPHOS), which is closely related to the features of the tumor microenvironment (TME). The HCC microenvironment consists of hypoxia, acidosis and immune suppression, and contributes to tumor glycolysis. In turn, the glycolysis of the tumor aggravates hypoxia, acidosis and immune suppression, and leads to tumor proliferation, angiogenesis, epithelial-mesenchymal transition (EMT), invasion and metastasis. In 2017, a mechanism underlying the effects of gluconeogenesis on inhibiting glycolysis and blockading HCC progression was proposed. Treating HCC by increasing gluconeogenesis has attracted increasing attention from scientists, but few articles have summarized it. In this review, we discuss the mechanisms associated with the TME, glycolysis and gluconeogenesis and the current treatments for HCC. We believe that a treatment combination of sorafenib with TME improvement and/or anti-Warburg therapies will set the trend of advanced HCC therapy in the future.

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The role of pyruvate kinase M2 in anticancer therapeutic treatments (Review)

Cited by 29 publications

References 101 publications

Protein kinase function of pyruvate kinase M2 and cancer

Protein kinase function of pyruvate kinase M2 and cancer

Compound 3K, a Specific Pyruvate Kinase M2 Inhibitor, Induces Autophagic Cell Death through the Disruption of the Glycolytic Pathway in Ovarian Cancer Cells

<p>Glucometabolic Reprogramming in the Hepatocellular Carcinoma Microenvironment: Cause and Effect</p>

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