Shikonin Inhibits Tumor Growth in Mice by Suppressing Pyruvate Kinase M2-mediated Aerobic Glycolysis

Zhao, Xiaoyue; Zhu, Yanan; Hu, Jianhua; Jiang, Lijia; Liu, Limin; Jia, Shaochang; Zen, Ke

doi:10.1038/s41598-018-31615-y

Cited by 105 publications

(83 citation statements)

References 32 publications

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“…There are many small molecule inhibitors and hormones that inhibit cell proliferation by targeting PKM2 (77)(78)(79). The inhibitors, namely shikonin and its analogs, flavonoid derivatives, and 2,3-dithiocarbamate substituted naphthoquinones bind to the allosteric site of PKM2, which leads to reduced glycolysis in cancer cells (77,(80)(81)(82).…”

Section: Pkm2 As a Potential Target For Cancer Therapymentioning

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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Section: Pkm2 As a Potential Target For Cancer Therapymentioning

confidence: 99%

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

et al. 2020

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“…These data further clarified the anti-tumor activity of shikonin in cervical cancer. The doses used in this were based on other studies, 10,[48][49][50] which showed substantial inhibitory effects without noticeable toxicity. Our findings suggested that shikonin suppressed growth of human cervical cancer via regulating miR-183-5p/Snail/Vimentin/E-cadherin signaling regulatory axis.…”

Section: Dovepressmentioning

confidence: 99%

<p>Regulations of miR-183-5p and Snail-Mediated Shikonin-Reduced Epithelial-Mesenchymal Transition in Cervical Cancer Cells</p>

Tang¹,

Liu²,

Zhang³

et al. 2020

DDDT

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Background: Shikonin, the main ingredient of Lithospermum erythrorhizon, has been reported to have antitumor effects via multiple targets and signaling pathways. However, the detailed mechanism underlying the effects in cervical cancer still remained unknown. Methods: MTT, wound-healing, transwell assays and flow cytometry experiments were used to measure cell growth, migration, invasion, and cell cycle analysis. Western blot was used to examine protein levels of Snail, Vimentin and E-cadherin. The expression level of miR-183-5p was measured via qRT-PCR. The E-cadherin promoter activity was detected via Secrete-PairTM Dual Luminescence Assay Kit. The transient transfection experiments were used for silencing of E-cadherin and overexpression of Snail genes. Tumor xenograft and bioluminescent imaging experiments were carried out to confirm the in vitro findings. Results: We showed that shikonin inhibited cell viability, migration and invasion, and induced cell cycle arrest in a dose-dependent manner in cervical cancer Hela and C33a cells. Mechanistically, we found that shikonin increased miR-183-5p expression and inhibited expression of transcription factor Snail protein. The mimics of miR-183-5p reduced, while the inhibitors of miR-183-5p reversed shikonin-inhibited Snail protein expression. In addition, shikonin decreased Vimentin, increased E-cadherin protein expressions and E-cadherin promoter activity, the latter was reversed in cells transfected with exogenous Snail overexpression vectors. Moreover, silencing of E-cadherin significantly abolished shikonin-inhibited cervical cancer cell growth. Similar findings were also observed in vivo using one xenograft mouse model. Conclusion: Our results show that shikonin inhibits EMT through inhibition of Snail and stimulation of miR-183-5p expressions, which resulted in induction of E-cadherin expression. Thus, blockade of EMT could be a novel mechanism underlying the anti-cervical cancer effects of shikonin.

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“…Several studies had shown that SK inhibits the growth of lung cancer cells and the glycolysis process of cervical cancer cells by inhibiting the expression of PKM2. 23,37 Therefore, we used q-PCR and Western blot to detect the expression of PKM2 after SK treatment. Our results demonstrated that of all glycolytic enzymes, expression of PKM2 protein and mRNA was reduced to the greatest extent with SK treatment in both LM3 and SMMC-7721 cells.…”

Section: Discussionmentioning

confidence: 99%

<p>Experimental Study of Hepatocellular Carcinoma Treatment by Shikonin Through Regulating PKM2</p>

Liu

et al. 2020

JHC

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These authors contributed equally to this workObjective: Shikonin is a natural product with many activities, including anti-cancer effects. Pyruvate kinase type M2 (PKM2) plays a crucial role in the growth of tumor cells. However, the effect of shikonin on PKM2 in hepatocellular carcinoma (HCC) is unclear. Methods: Cell viability, apoptosis level, glucose uptake, and lactate production were detected in HCC cells. Lentivirus-overexpressed and -shRNA of PKM2 were used to verify the key target of shikonin. A xenograft mouse model was used to detect the efficacy of shikonin and its combination with sorafenib in vivo. Results: Shikonin inhibited proliferation and glycolysis and induced apoptosis in HCC cells. Either PKM2-overexpressed or PKM2-shRNA alleviated or enhanced this effect. The results of CCK-8 showed that shikonin significantly inhibited cell viability of HCC cells. The levels of glucose uptake and lactate production were dramatically decreased by shikonin-treated. Results of flow cytometry and Western blot showed that the levels of apoptosis of HCC cells were significantly increased in a dose-dependent manner after shikonin treatment. In addition, shikonin enhanced the anti-cancer effect of sorafenib in vitro and in vivo. Our results showed that SK combined with sorafenib markedly inhibits tumor growth in HCCtransplanted nude mice compared to SK or sorafenib alone. Conclusion: By inhibiting PKM2, shikonin inhibited proliferation and glycolysis and induced cell apoptosis in HCC cells. The effect of shikonin on tumor cell proliferation, apoptosis and glycolsis will make it promising drug for HCC patients.

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Shikonin Inhibits Tumor Growth in Mice by Suppressing Pyruvate Kinase M2-mediated Aerobic Glycolysis

Cited by 105 publications

References 32 publications

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

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

<p>Regulations of miR-183-5p and Snail-Mediated Shikonin-Reduced Epithelial-Mesenchymal Transition in Cervical Cancer Cells</p>

<p>Experimental Study of Hepatocellular Carcinoma Treatment by Shikonin Through Regulating PKM2</p>

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