Knockdown of Pyruvate Kinase M2 Inhibits Cell Proliferation, Metabolism, and Migration in Renal Cell Carcinoma

Emerging evidence indicates that the activity of pyruvate kinase M2 (PKM2) isoform is crucial for the survival of tumor cells. However, the molecular mechanism underlying the function of PKM2 in renal cancer is undetermined. Here, we reveal the overexpression of PKM2 in the proximal tubule of renal tumor tissues from 70 cases of patients with renal carcinoma. The functional role of PKM2 in human renal cancer cells following small-interfering RNA-mediated PKM2 knockdown, which retarded 786-O cell growth was examined. Targeting PKM2 affected the protein kinase B (AKT)/mechanistic target of the rapamycin 1 (mTOR) pathway, and downregulated the expression of glycolytic enzymes, including lactate dehydrogenase A and glucose transporter-1, and other downstream signaling key proteins. PKM2 knockdown changed glycolytic metabolism, mitochondrial function, adenosine triphosphate (ATP) level, and intracellular metabolite formation and significantly reduced 786-O cell migration and invasion. Acridine orange and monodansylcadaverine staining, immunocytochemistry, and immunoblotting analyses revealed the induction of autophagy in renal cancer cells following PKM2 knockdown. This is the first study to indicate PKM2/AKT/mTOR as an important regulatory axis mediating the changes in the metabolism of renal cancer cells.

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Relationship between 18-F-fluoro-deoxy-d-glucose uptake and expression of glucose transporter 1 and pyruvate kinase M2 in intrahepatic cholangiocarcinoma

Digestive and Liver Disease ◽

10.1016/j.dld.2015.03.017 ◽

2015 ◽

Vol 47 (7) ◽

pp. 590-596 ◽

Cited By ~ 9

Author(s):

Hideki Suzuki ◽

Mina Komuta ◽

Altan Bolog ◽

Takehiko Yokobori ◽

Satoshi Wada ◽

...

Keyword(s):

Glucose Uptake ◽

Pyruvate Kinase ◽

Intrahepatic Cholangiocarcinoma ◽

Glucose Transporter ◽

Glucose Transporter 1 ◽

Pyruvate Kinase M2

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Biological Evaluation of Oxindole Derivative as a Novel Anticancer Agent against Human Kidney Carcinoma Cells

Biomolecules ◽

10.3390/biom10091260 ◽

2020 ◽

Vol 10 (9) ◽

pp. 1260

Author(s):

Prasanta Dey ◽

Amit Kundu ◽

Sang Hoon Han ◽

Kyeong-Seok Kim ◽

Jae Hyeon Park ◽

...

Keyword(s):

Cancer Cells ◽

Renal Cancer ◽

Glucose Transporter ◽

Tumor Development ◽

Xenograft Model ◽

Human Kidney ◽

Biological Evaluation ◽

Glucose Transporter 1 ◽

Cycle Arrest ◽

The Usa

Renal cell carcinoma has emerged as one of the leading causes of cancer-related deaths in the USA. Here, we examined the anticancer profile of oxindole derivatives (SH-859) in human renal cancer cells. Targeting 786-O cells by SH-859 inhibited cell growth and affected the protein kinase B/mechanistic target of rapamycin 1 pathway, which in turn downregulated the expression of glycolytic enzymes, including lactate dehydrogenase A and glucose transporter-1, as well as other signaling proteins. Treatment with SH-859 altered glycolysis, mitochondrial function, and levels of adenosine triphosphate and cellular metabolites. Flow cytometry revealed the induction of apoptosis and G0/G1 cell cycle arrest in renal cancer cells following SH-859 treatment. Induction of autophagy was also confirmed after SH-859 treatment by acridine orange and monodansylcadaverine staining, immunocytochemistry, and Western blot analyses. Finally, SH-859 also inhibited the tumor development in a xenograft model. Thus, SH-859 can serve as a potential molecule for the treatment of human renal carcinoma.

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The Transcription Factor Creb is Involved in Sorafenib-Inhibited Renal Cancer Cell Proliferation, Migration and Invasion

Acta Pharmaceutica ◽

10.2478/acph-2018-0033 ◽

2018 ◽

Vol 68 (4) ◽

pp. 497-506 ◽

Cited By ~ 3

Author(s):

Shuaishuai Huang ◽

Pinger Cui ◽

Shuangxia Lin ◽

Xuping Yao ◽

Xue Wang ◽

...

Keyword(s):

Cell Proliferation ◽

Cancer Cells ◽

Renal Cancer ◽

Migration And Invasion ◽

Dependent Manner ◽

Inhibition Of Proliferation ◽

Sorafenib Treatment ◽

Invasion And Migration ◽

Element Binding Protein ◽

And Migration

Abstract Our previous reports showed that the cyclic-AMP-response element-binding protein (CREB) served as a proto-oncogene in the process of tumorigenesis and mediated the growth and metastatic activity of renal cancer cells. Our study, therefore, explored the role of CREB in sorafenib- -inhibited cell proliferation, migration and invasion. Renal cancer cells were cultured in medium containing sorafenib for 12, 24, 48 and 72 h. The MTT assay was used to study the cytotoxic effects of sorafenib. Cell invasion and migration were assayed in wound healing and transwell experiments, respectively. Protein expression levels were evaluated by western blotting. The results show that sorafenib treatment decreased cell viability in a dose- and time-dependent manner. Sorafenib inhibited cell migration and invasion and decreased the expression of MMP-2 and MMP-9. Moreover, addition of the recombinant plasmid pCI-neo/ CREB (PN) reversed the sorafenib-induced inhibition of cell proliferation, migration and invasion. These results show that CREB is associated with the sorafenib-induced inhibition of proliferation, migration and invasion.

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Isothiocyanate From Moringa oleifera Seeds Inhibits the Growth and Migration of Renal Cancer Cells by Regulating the PTP1B-dependent Src/Ras/Raf/ERK Signaling Pathway

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.790618 ◽

2022 ◽

Vol 9 ◽

Author(s):

Jing Xie ◽

Ying-Yan Qian ◽

Yang Yang ◽

Lin-Jie Peng ◽

Jia-Ying Mao ◽

...

Keyword(s):

Cell Cycle ◽

Cancer Cells ◽

Signaling Pathway ◽

Renal Cancer ◽

Moringa Oleifera ◽

Hydrophobic Interactions ◽

Erk Signaling ◽

Migration And Invasion ◽

A431 Cells ◽

And Migration

Moringa oleifera Lam. is a tropical and subtropical plant that has been used for centuries as both food and traditional medicine. 4-[(α-L-Rhamnosyloxy) benzyl] isothiocyanate (MIC-1) is an active substance in M. oleifera, with anti-cancer activity. However, whether MIC-1 exerts anti-renal cancer effects is unknown. Therefore, the aim of the present study was to evaluate the effects of MIC-1 on the growth and migration of renal cell carcinoma (RCC) cells and to identify the putative underlying mechanism. We found that, among 30 types of cancer cells, MIC-1 exerted the strongest growth inhibitory effects against 786-O RCC cells. In addition, MIC-1 (10 μM) significantly inhibited the growth of five RCC cell lines, including 786-O, OSRC-2, 769-P, SK-NEP-1, and ACHN cells, but was not toxic to normal renal (HK2) cells. Also, MIC-1 suppressed 786-O and 769-P cell migration and invasion abilities, and reduced the expression of matrix metalloproteinase (MMP)-2 and MMP-9. Furthermore, MIC-1 induced apoptosis and cell cycle arrest, increased Bax/Bcl-2 ratio, and decreased cell cycle-related protein expression in 786-O cells and 769-P cells. Molecular docking and small-molecule interaction analyses with PTP1B both showed that MIC-1 inhibited PTP1B activity by binding to its active site through hydrogen bonding and hydrophobic interactions. Additionally, MIC-1 could suppress the growth and migration of 786-O cells by inhibiting PTP1B-mediated activation of the Src/Ras/Raf/ERK signaling pathway. In vivo experiments further showed that MIC-1 markedly inhibited the growth of xenograft tumors in mice, and greatly increased Bax/Bcl-2 ratio in tumor tissues. In addition, MIC-1 had no effect on the PTP1B-dependent Src/Ras/Raf/ERK signaling pathway in HCT-116 cells, Hep-G2 cells, and A431 cells. Overall, our data showed that MIC-1 could be a promising, non-toxic, natural dietary supplement for the prevention and treatment of renal cancer.

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Breaking Glucose Transporter 1/Pyruvate Kinase M2 Glycolytic Loop Is Required for Cantharidin Inhibition of Metastasis in Highly Metastatic Breast Cancer

Frontiers in Pharmacology ◽

10.3389/fphar.2019.00590 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 8

Author(s):

Yanhong Pan ◽

Qian Zheng ◽

Wenting Ni ◽

Zhonghong Wei ◽

Suyun Yu ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Pyruvate Kinase ◽

Glucose Transporter ◽

Metastatic Breast ◽

Glucose Transporter 1 ◽

Pyruvate Kinase M2

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Glycolysis Inhibition as a Strategy for Hepatocellular Carcinoma Treatment?

Current Cancer Drug Targets ◽

10.2174/1568009618666180430144441 ◽

2018 ◽

Vol 19 (1) ◽

pp. 26-40 ◽

Cited By ~ 9

Author(s):

A.P. Alves ◽

A.C. Mamede ◽

M.G. Alves ◽

P.F. Oliveira ◽

S.M. Rocha ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cancer Cells ◽

Anticancer Agents ◽

Glucose Transporter ◽

Public Health Problem ◽

High Morbidity ◽

Curative Intent ◽

Malignant Liver Tumor ◽

Glucose Transporter 1 ◽

Inhibition Of Glycolysis

Hepatocellular carcinoma (HCC) is the most frequently detected primary malignant liver tumor, representing a worldwide public health problem due to its high morbidity and mortality rates. The HCC is commonly detected in advanced stage, precluding the use of treatments with curative intent. For this reason, it is crucial to find effective therapies for HCC. Cancer cells have a high dependence of glycolysis for ATP production, especially under hypoxic environment. Such dependence provides a reliable possible strategy to specifically target cancer cells based on the inhibition of glycolysis. HCC, such as other cancer types, presents a clinically well-known upregulation of several glycolytic key enzymes and proteins, including glucose transporters particularly glucose transporter 1 (GLUT1). Such enzymes and proteins constitute potential targets for therapy. Indeed, for some of these targets, several inhibitors were already reported, such as 2-Deoxyglucose, Imatinib or Flavonoids. Although the inhibition of glycolysis presents a great potential for an anticancer therapy, the development of glycolytic inhibitors as a new class of anticancer agents needs to be more explored. Herein, we propose to summarize, discuss and present an overview on the different approaches to inhibit the glycolytic metabolism in cancer cells, which may be very effective in the treatment of HCC.

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Long non-coding RNA XIST regulates ovarian cancer progression via modulating miR-335/BCL2L2 axis

World Journal of Surgical Oncology ◽

10.1186/s12957-021-02274-7 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Qingjuan Meng ◽

Ningning Wang ◽

Guanglan Duan

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Ovarian Cancer Cells ◽

Human Ovarian Cancer ◽

Invasion And Migration ◽

Non Coding Rna ◽

And Migration ◽

Long Non Coding Rna

Abstract Background X inactivation-specific transcript (XIST) is the long non-coding RNA (lncRNA) related to cancer, which is involved in the development and progression of various types of tumor. However, up to now, the exact role and molecular mechanism of XIST in the progression of ovarian cancer are not clear. We studied the function of XIST in ovarian cancer cells and clinical tumor specimens. Methods RT-qPCR was performed to detect the expression levels of miR-335 and BCL2L2 in ovarian cancer cells and tissues. MTT and transwell assays were carried out to detect cell proliferation, migration, and invasion abilities. Western blot was performed to analyze the expression level of BCL2L2. The interaction between miR-335 and XIST/BCL2L2 was confirmed using a luciferase reporter assay. Results The inhibition of XIST can inhibit the proliferation invasion and migration of human ovarian cancer cells. In addition, the miR-335/BCL2L2 axis was involved in the functions of XIST in ovarian cancer cells. These results suggested that XIST could regulate tumor proliferation and invasion and migration via modulating miR-335/BCL2L2. Conclusion XIST might be a carcinogenic lncRNA in ovarian cancer by regulating miR-335, and it can serve as a therapeutic target in human ovarian cancer.

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