6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase-2 Regulates TP53-Dependent Paclitaxel Sensitivity in Ovarian and Breast Cancers

Yang, Hailing; Zhang, Shu; Jiang, Yongying; Mao, Weiqun; Pang, Lan; Redwood, Abena B.; Jeter-Jones, Sabrina; Jennings, Nicholas B.; Ornelas, Argentina; Zhou, Jinhua; Rodríguez-Aguayo, Cristian; Bartholomeusz, Geoffrey; Iles, La Kesla; Zacharias, Niki M.; Millward, Steven W.; López-Berestein, Gabriel; Le, Xiao Feng; Ahmed, Ahmed A.; Piwnica‐Worms, Helen; Sood, Anil K.; Bast, Robert C.; Lü, Zhen

doi:10.1158/1078-0432.ccr-18-3448

Cited by 27 publications

(16 citation statements)

References 46 publications

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“…Mitophagy is also described as a possible mechanism for preventing ROS production [ 45 ]. And cancer cells were likely to be more sensitive to the additional oxidative damage promoted by ROS [ 46 – 48 ]. Therefore, we presumed that hypoxia induced hyperactivated mitophagy may decrease ROS production and then result in sorafenib insensitivity.…”

Section: Discussionmentioning

confidence: 99%

Mitophagy promotes sorafenib resistance through hypoxia-inducible ATAD3A dependent Axis

Wang

Liu

et al. 2020

J Exp Clin Cancer Res

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Background The identification of novel targets for recovering sorafenib resistance is pivotal for Hepatocellular carcinoma (HCC) patients. Mitophagy is the programmed degradation of mitochondria, and is likely involved in drug resistance of cancer cells. Here, we identified hyperactivated mitophagy is essential for sorafenib resistance, and the mitophagy core regulator gene ATAD3A (ATPase family AAA domain containing 3A) was down regulated in hypoxia induced resistant HCC cells. Blocking mitophagy may restore the sorafenib sensitivity of these cells and provide a new treatment strategy for HCC patients. Methods Hypoxia induced sorafenib resistant cancer cells were established by culturing under 1% O2 with increasing drug treatment. RNA sequencing was conducted in transfecting LM3 cells with sh-ATAD3A lentivirus. Subsequent mechanistic studies were performed in HCC cell lines by manipulating ATAD3A expression isogenically where we evaluated drug sensitivity, molecular signaling events. In vivo study, we investigated the combined treatment effect of sorafenib and miR-210-5P antagomir. Results We found a hyperactivated mitophagy regulating by ATAD3A-PINK1/PARKIN axis in hypoxia induced sorafenib resistant HCC cells. Gain- and loss- of ATAD3A were related to hypoxia-induced mitophagy and sorafenib resistance. In addition, ATAD3A is a functional target of miR-210-5p and its oncogenic functions are likely mediated by increased miR-210-5P expression. miR-210-5P was upregulated under hypoxia and participated in regulating sorafenib resistance. In vivo xenograft assay showed that miR-210-5P antagomir combined with sorafenib abrogated the tumorigenic effect of ATAD3A down-regulation in mice. Conclusions Loss of ATAD3A hyperactivates mitophagy which is a core event in hypoxia induced sorafenib resistance in HCC cells. Targeting miR-210-5P-ATAD3A axis is a novel therapeutic target for sorafenib-resistant HCC.

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Section: Discussionmentioning

confidence: 99%

Mitophagy promotes sorafenib resistance through hypoxia-inducible ATAD3A dependent Axis

Wang

Liu

et al. 2020

J Exp Clin Cancer Res

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“…Thus, the PFKFB family enzymes are promising targets in anti-cancer therapy in order to combat tumor growth, invasion, and metastasis. For example, silencing the PFKFB2 gene has been shown to significantly inhibit ovarian and breast cancer growth and to enhance paclitaxel sensitivity and patient survival [95].…”

Section: Enhancement Of Glycolysismentioning

confidence: 99%

Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK

Moldogazieva

Mokhosoev

Terentiev

2020

Cancers

117

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It has been long recognized that cancer cells reprogram their metabolism under hypoxia conditions due to a shift from oxidative phosphorylation (OXPHOS) to glycolysis in order to meet elevated requirements in energy and nutrients for proliferation, migration, and survival. However, data accumulated over recent years has increasingly provided evidence that cancer cells can revert from glycolysis to OXPHOS and maintain both reprogrammed and oxidative metabolism, even in the same tumor. This phenomenon, denoted as cancer cell metabolic plasticity or hybrid metabolism, depends on a tumor micro-environment that is highly heterogeneous and influenced by an intensity of vasculature and blood flow, oxygen concentration, and nutrient and energy supply, and requires regulatory interplay between multiple oncogenes, transcription factors, growth factors, and reactive oxygen species (ROS), among others. Hypoxia-inducible factor-1 (HIF-1) and AMP-activated protein kinase (AMPK) represent key modulators of a switch between reprogrammed and oxidative metabolism. The present review focuses on cross-talks between HIF-1, glucose transporters (GLUTs), and AMPK with other regulatory proteins including oncogenes such as c-Myc, p53, and KRAS; growth factor-initiated protein kinase B (PKB)/Akt, phosphatidyl-3-kinase (PI3K), and mTOR signaling pathways; and tumor suppressors such as liver kinase B1 (LKB1) and TSC1 in controlling cancer cell metabolism. The multiple switches between metabolic pathways can underlie chemo-resistance to conventional anti-cancer therapy and should be taken into account in choosing molecular targets to discover novel anti-cancer drugs.

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“…The changes in key enzymes can lead to an enhanced glycolytic ability, promote glucose uptake into tumor cells and increase the accumulation of lactic acid, thus further supporting tumor growth and development ( 21 ). 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB2) is an enzyme that regulates the synthesis and degradation of fructose-2,6-bisphosphate (Fru-2, 6-P2), which is widely expressed in a variety of cancer cells, such as ovarian, breast and pancreatic cancer cells ( 22 , 23 ). By regulating the expression of Fru-2, 6-P2 (a signaling metabolite that participates in glycolysis), the PFKFB family has been found to regulate intracellular glycolysis in cancer by acting as an oncogene ( 24 , 25 ).…”

Section: Introductionmentioning

confidence: 99%

Shikonin inhibits the Warburg effect, cell proliferation, invasion and migration by downregulating PFKFB2 expression in lung cancer

Sha

Liu

et al. 2021

Mol Med Rep

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Lung cancer is one of the most lethal diseases and therefore poses a significant threat to human health. The Warburg effect, which is the observation that cancer cells predominately produce energy through glycolysis, even under aerobic conditions, is a hallmark of cancer. 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB) is an important regulator of glycolysis. Shikonin is a Traditional Chinese herbal medicine, which has been reported to exert antitumor effects. The present study aimed to investigate the anticancer activity of shikonin in lung cancer. Cell Counting Kit-8 (CCK-8) and colony formation assays were used to analyze proliferation in A549 and H446 cells. Wound healing and Transwell assays were used to measure migration and invasion in A549 and H446 cells. Cell apoptosis was analyzed using flow cytometry. Lactate levels, glucose uptake and cellular ATP levels were measured using their corresponding commercial kits. Western blotting was performed to analyze the protein expression levels of key enzymes involved in aerobic glucose metabolism. Reverse transcription-quantitative PCR was used to analyze the mRNA expression levels of PFKFB2. The results of the present study revealed that PFKFB2 expression levels were significantly upregulated in NSCLC tissues. Shikonin treatment decreased the proliferation, migration, invasion, glucose uptake, lactate levels, ATP levels and PFKFB2 expression levels and increased apoptosis in lung cancer cells in a dose-dependent manner. The overexpression of PFKFB2 increased the proliferation, migration, glucose uptake, lactate levels and ATP levels in lung cancer cells, while the knockdown of PFKFB2 expression exerted the opposite effects. Moreover, there were no significant differences in lung cancer cell migration, apoptosis, glucose uptake, lactate levels and ATP levels between cells with knocked down PFKFB2 expression or treated with shikonin and the knockdown of PFKFB2 in cells treated with shikonin. In conclusion, the results of the present study revealed that shikonin inhibited the Warburg effect and exerted antitumor activity in lung cancer cells, which was associated with the downregulation of PFKFB2 expression.

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6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase-2 Regulates TP53-Dependent Paclitaxel Sensitivity in Ovarian and Breast Cancers

Cited by 27 publications

References 46 publications

Mitophagy promotes sorafenib resistance through hypoxia-inducible ATAD3A dependent Axis

Mitophagy promotes sorafenib resistance through hypoxia-inducible ATAD3A dependent Axis

Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK

Shikonin inhibits the Warburg effect, cell proliferation, invasion and migration by downregulating PFKFB2 expression in lung cancer

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