Fructose-Bisphosphate Aldolase A Regulates Hypoxic Adaptation in Hepatocellular Carcinoma and Involved with Tumor Malignancy

Li, Xin; Feng, Jinteng; Zhong, Guangming; Chen, Bin; Yu, Jiang; Xin, Ming-jun; Wang, Jiandong; An, Lingxuan; Wei, Ji-Chao; Wu, Liqun

doi:10.1007/s10620-019-05642-2

Cited by 28 publications

(17 citation statements)

References 33 publications

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“…The increased expression of ALDOA is significantly associated with the development and poor prognosis of various tumors. [15][16][17][26][27][28][29][30] In our study, we found that ALDOA overexpression could promote the proliferation and cell cycle progression of PCa cells and inhibited the apoptosis of PCa cells in vitro. Meanwhile, ALDOA overexpression promoted tumor growth of PCa in nude mice in vivo.…”

Section: Discussionsupporting

confidence: 53%

The ALDOA Metabolism Pathway as a Potential Target for Regulation of Prostate Cancer Proliferation

Kuang¹,

Liang²,

Zhuo³

et al. 2021

OTT

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Background: ALDOA plays an essential role in cancer progression in different human cancers; however, its function has not been understood in prostate cancer (PCa). Methods: Associations of ALDOA expression with clinicopathological features and patient prognosis in PCa were evaluated based on data obtained from the Taylor database and our clinical tissue microarray. The potential roles of ALDOA in malignant progression were verified using a series of in vivo and in vitro experiments after stable ALDOA overexpression and knockdown in DU145 and PC3 cell lines. An aldolase A inhibitor was used to determine the effects of inhibition of ALDOA on PCa cell proliferation. Results: Higher expression of ALDOA was positively correlated with the incidence of postoperative metastasis and biochemical recurrence (BCR) and may predict poor prognosis in PCa patients. In vivo experiments demonstrated that overexpression of ALDOA could significantly promote cell proliferation, prolong the cell cycle, and significantly reduce the apoptosis rate of PCa cells. Knockdown of expression of ALDOA could inhibit the proliferation and shorten the cell cycle of PCa cells significantly, with no significant effects on cell apoptosis (P > 0.05). In vitro experiments showed that overexpression of ALDOA could significantly promote tumor growth (P < 0.05), while treatment with the Aldolase A inhibitor naphthol AS-E phosphate dose-dependently suppressed the growth of PCa cells (P < 0.01). The analysis of datasets from the Taylor database showed that there was negative regulatory relationship between the expression of ALDOA and MYPT1 (P < 0.001). Conclusion:Our study revealed that ALDOA played an important role in the progression of PCa. The MYPT1-ALDOA signaling axis may be a new target for the clinical treatment of PCa patients given its negative regulatory relationship. Our study suggests that Aldolase A inhibitors may represent a novel approach to inhibit the growth of PCa.

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Section: Discussionsupporting

confidence: 53%

The ALDOA Metabolism Pathway as a Potential Target for Regulation of Prostate Cancer Proliferation

Kuang¹,

Liang²,

Zhuo³

et al. 2021

OTT

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“…Under hypoxic conditions, both genes were significantly down-regulated by regorafenib and no further decrease was induced by the combination. In contrast, the expression of aldolase A, which is up-regulated in HCC tissues and correlates with HCC malignancy (46), was significantly decreased by the combination in comparison with control or single agent treatments (Figure 7C). Then, we investigated the activation/expression of pyruvate kinase M2 (PKM2), which is predominantly expressed as a dimeric form with low PK activity in cancer cells (47).…”

Section: Effects Of the Simultaneous Combination Of Palbociclib With mentioning

confidence: 96%

Simultaneous Combination of the CDK4/6 Inhibitor Palbociclib With Regorafenib Induces Enhanced Anti-tumor Effects in Hepatocarcinoma Cell Lines

et al. 2020

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Advanced hepatocarcinoma (HCC) is an aggressive malignancy with poor prognosis and limited treatment options. Alterations of the cyclin D-CDK4/6-Rb pathway occur frequently in HCC, providing the rationale for its targeting at least in a molecular subset of HCC. In a panel of HCC cell lines, we investigated whether the CDK4/6 inhibitor palbociclib might improve the efficacy of regorafenib, a powerful multi-kinase inhibitor approved as second-line treatment for advanced HCC after sorafenib failure and currently under clinical investigation as first-line therapy in combination with immunotherapy. In Rb-proficient cells, the simultaneous drug combination, but not the sequential schedules, inhibited cell proliferation, either in short or in long-term experiments, and induced cell death more strongly than individual treatments. Moreover, the combination significantly reduced spheroid cell growth and inhibited cell migration/invasion. The superior efficacy of palbociclib plus regorafenib emerged also under hypoxia and was associated with a significant down-regulation of CDK4/6-Rb-myc and mTORC1/p70S6K signaling. Moreover, regorafenib suppressed palbociclib-induced expression of cyclin D1 contributing to the cytotoxic effects of the combination. Besides these inhibitory effects on cell viability/proliferation, palbociclib and regorafenib reduced glucose uptake, although this effect was dependent on the cell model and on the oxygen availability (normoxia or hypoxia). Palbociclib and regorafenib combination impaired glucose uptake and utilization, down-regulating basal and hypoxia-induced expression of HIF-1α, HIF-2α, GLUT-1, and MCT4 proteins as well as the activity/expression of glycolytic enzymes (HK2, PFKP, aldolase A, PKM2). In addition, regorafenib alone reduced mitochondrial respiration. The combined treatment impaired glucose metabolism and respiration without enhancing the effects of the single agents. Our findings provide pre-clinical evidence for the effectiveness of palbociclib and regorafenib combination in HCC cell models.

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“…Despite the strong evidence that both proteins may have a role in PDAC progression and chemoresistance, there are no studies exploring this area. However, in other tumor types it was found that FBA correlates with the aggressiveness of the tumor [ 346 ]. Therefore, the use of either FBA or G3P as targets for new chemicals should be encouraged, with the objective to reduce the cancer-associated drug resistance.…”

Section: The Tumor Metabolic Microenvironment Promotes Resistance Against Chemotherapymentioning

confidence: 99%

Tumor Microenvironment Features and Chemoresistance in Pancreatic Ductal Adenocarcinoma: Insights into Targeting Physicochemical Barriers and Metabolism as Therapeutic Approaches

Carvalho

Molfetta

Greco

et al. 2021

Cancers

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Currently, the median overall survival of PDAC patients rarely exceeds 1 year and has an overall 5-year survival rate of about 9%. These numbers are anticipated to worsen in the future due to the lack of understanding of the factors involved in its strong chemoresistance. Chemotherapy remains the only treatment option for most PDAC patients; however, the available therapeutic strategies are insufficient. The factors involved in chemoresistance include the development of a desmoplastic stroma which reprograms cellular metabolism, and both contribute to an impaired response to therapy. PDAC stroma is composed of immune cells, endothelial cells, and cancer-associated fibroblasts embedded in a prominent, dense extracellular matrix associated with areas of hypoxia and acidic extracellular pH. While multiple gene mutations are involved in PDAC initiation, this desmoplastic stroma plays an important role in driving progression, metastasis, and chemoresistance. Elucidating the mechanisms underlying PDAC resistance are a prerequisite for designing novel approaches to increase patient survival. In this review, we provide an overview of the stromal features and how they contribute to the chemoresistance in PDAC treatment. By highlighting new paradigms in the role of the stromal compartment in PDAC therapy, we hope to stimulate new concepts aimed at improving patient outcomes.

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Fructose-Bisphosphate Aldolase A Regulates Hypoxic Adaptation in Hepatocellular Carcinoma and Involved with Tumor Malignancy

Cited by 28 publications

References 33 publications

The ALDOA Metabolism Pathway as a Potential Target for Regulation of Prostate Cancer Proliferation

The ALDOA Metabolism Pathway as a Potential Target for Regulation of Prostate Cancer Proliferation

Simultaneous Combination of the CDK4/6 Inhibitor Palbociclib With Regorafenib Induces Enhanced Anti-tumor Effects in Hepatocarcinoma Cell Lines

Tumor Microenvironment Features and Chemoresistance in Pancreatic Ductal Adenocarcinoma: Insights into Targeting Physicochemical Barriers and Metabolism as Therapeutic Approaches

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