Inhibition of pyruvate carboxylase by 1α,25-dihydroxyvitamin D promotes oxidative stress in early breast cancer progression

Wilmanski, Tomasz; Zhou, Xuanzhu; Zheng, Wei; Shinde, Aparna; Donkin, Shawn S.; Wendt, Michael K.; Burgess, John; Teegarden, Dorothy

doi:10.1016/j.canlet.2017.09.045

Cited by 68 publications

(58 citation statements)

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“…Piotrowska A et al report that 1a,25 (OH) 2 D 3 promotes the oxidative damage of H 2 O 2 on human keratinocytes (Piotrowska et al, 2016). In the present study, consistent with enhancement of oxidative stress in breast cancer (Wilmanski et al, 2017), we found that 1a,25(OH) 2 D 3 promoted ROS levels in lung and ovarian cancer cells.…”

Section: Discussionsupporting

confidence: 91%

1α,25(OH)2D3 Radiosensitizes Cancer Cells by Activating the NADPH/ROS Pathway

Nie

et al. 2020

Front. Pharmacol.

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The radioresistance of tumors affect the outcome of radiotherapy. Accumulating data suggest that 1a,25(OH) 2 D 3 is a potential anti-oncogenic molecule in various cancers. In the present study, we investigated the radiosensitive effects and underlying mechanisms of 1a,25(OH) 2 D 3 in vitro and in vivo. We found that 1a,25(OH) 2 D 3 enhanced the radiosensitivity of lung cancer and ovarian cancer cells by promoting the NADPH oxidase-ROS-apoptosis axis. Compared to the group that only received radiation, the survival fraction and selfrenewal capacity of cancer cells treated with a combination of 1a,25(OH) 2 D 3 and radiation were decreased. Both apoptosis and ROS were significantly increased in the combination group compared with the radiation only group. Moreover, N-acetyl-L-cysteine, a scavenger of intracellular ROS, reversed the apoptosis and ROS induced by 1a,25(OH) 2 D 3 , indicating that 1a,25(OH) 2 D 3 enhanced the radiosensitivity of cancer cells in vitro by promoting ROSinduced apoptosis. Moreover, our results demonstrated that 1a,25(OH) 2 D 3 promoted the ROS level via activating NADPH oxidase complexes, NOX4, p22 phox , and p47 phox. In addition, knockdown of the vitamin D receptor (VDR) abolished the radiosensitization of 1a,25(OH) 2 D 3 , which confirmed that 1a,25(OH) 2 D 3 radiosensitized tumor cells that depend on VDR. Similarly, our study also evidenced that vitamin D 3 enhanced the radiosensitivity of cancer cells in vivo and extended the overall survival of mice with tumors. In summary, these results demonstrate that 1a,25(OH) 2 D 3 enhances the radiosensitivity depending on VDR and activates the NADPH oxidase-ROS-apoptosis axis. Our findings suggest that 1a,25 (OH) 2 D 3 in combination with radiation enhances lung and ovarian cell radiosensitivity, potentially providing a novel combination therapeutic strategy.

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Section: Discussionsupporting

confidence: 91%

1α,25(OH)2D3 Radiosensitizes Cancer Cells by Activating the NADPH/ROS Pathway

Nie

et al. 2020

Front. Pharmacol.

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“…Consistent with our recent studies we observed an enhanced sensitivity to H 2 O 2 upon depletion of PC (Fig 7d and 7e; [29]).…”

Section: Pc Is Required For the Metabolic Plasticity Of Metastatic Brsupporting

confidence: 93%

Pyruvate carboxylase supports the pulmonary tropism of metastatic breast cancer

Shinde

Wilmanski

Chen

et al. 2018

Preprint

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Abstract:Background: Overcoming systemic dormancy and initiating secondary tumor grow under unique microenvironmental conditions is a major rate-limiting step in metastatic progression.Disseminated tumor cells encounter major changes in nutrient supplies and oxidative stresses compared to the primary tumor and must demonstrate significant metabolic plasticity to adapt to specific metastatic sites. Recent studies suggest that differential utilization of pyruvate sits as a critical node in determining the organotropism of metastatic breast cancer. Pyruvate carboxylase (PC) is key enzyme that converts pyruvate into oxaloacetate for utilization in gluconeogenesis and replenishment of the TCA cycle. Methods:Patient survival was analyzed with respect to gene copy number alterations and differential mRNA expression levels of PC. Expression of PC was analyzed in the MCF-10A, D2-HAN and the 4T1 breast cancer progression series under in vitro and in vivo growth conditions. PC expression was depleted via shRNAs and the impact on in vitro cell growth, mammary fat pad tumor growth, and pulmonary and non-pulmonary metastasis was assessed by bioluminescent imaging. Changes in glycolytic capacity, oxygen consumption and response to oxidative stress were quantified upon PC depletion.Results: Genomic copy number increases in PC were observed in 16-30% of metastatic breast cancer patients. High expression of PC mRNA was associated with decreased patient survival in the MCTI and METABRIC patient datasets. Enhanced expression of PC was not recapitulated in breast cancer progression models when analyzed under glucose-rich in vitro culture conditions. In contrast, PC expression was dramatically enhanced upon glucose deprivation and in vivo in pulmonary metastases. Depletion of PC led to a dramatic decrease in 4T1 pulmonary metastasis but did not affect orthotopic primary tumor growth. Tail vein inoculations confirmed the role of PC in facilitating pulmonary, but not extra-pulmonary tumor initiation. PC-depleted cells . CC-BY-NC 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/317743 doi: bioRxiv preprint first posted online May. 15, 2018; 3 demonstrated a decrease in glycolytic capacity and oxygen consumption rates and an enhanced sensitivity to oxidative stress. Conclusions:Our studies indicate that PC is specifically required for the growth of breast cancer that has disseminated to the lungs. Overall, these findings point to the potential of targeting PC for the treatment of pulmonary metastatic breast cancer.

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“…Consistent with our recent studies we observed an enhanced sensitivity to H 2 O 2 upon depletion of PC (Fig. 7d and e ; [ 28 ]).…”

Section: Resultssupporting

confidence: 93%

Pyruvate carboxylase supports the pulmonary tropism of metastatic breast cancer

et al. 2018

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BackgroundOvercoming systemic dormancy and initiating secondary tumor grow under unique microenvironmental conditions is a major rate-limiting step in metastatic progression. Disseminated tumor cells encounter major changes in nutrient supplies and oxidative stresses compared to the primary tumor and must demonstrate significant metabolic plasticity to adapt to specific metastatic sites. Recent studies suggest that differential utilization of pyruvate sits as a critical node in determining the organotropism of metastatic breast cancer. Pyruvate carboxylase (PC) is key enzyme that converts pyruvate into oxaloacetate for utilization in gluconeogenesis and replenishment of the TCA cycle.MethodsPatient survival was analyzed with respect to gene copy number alterations and differential mRNA expression levels of PC. Expression of PC was analyzed in the MCF-10A, D2-HAN and the 4 T1 breast cancer progression series under in vitro and in vivo growth conditions. PC expression was depleted via shRNAs and the impact on in vitro cell growth, mammary fat pad tumor growth, and pulmonary and non-pulmonary metastasis was assessed by bioluminescent imaging. Changes in glycolytic capacity, oxygen consumption, and response to oxidative stress were quantified upon PC depletion.ResultsGenomic copy number increases in PC were observed in 16–30% of metastatic breast cancer patients. High expression of PC mRNA was associated with decreased patient survival in the MCTI and METABRIC patient datasets. Enhanced expression of PC was not recapitulated in breast cancer progression models when analyzed under glucose-rich in vitro culture conditions. In contrast, PC expression was dramatically enhanced upon glucose deprivation and in vivo in pulmonary metastases. Depletion of PC led to a dramatic decrease in 4 T1 pulmonary metastasis, but did not affect orthotopic primary tumor growth. Tail vein inoculations confirmed the role of PC in facilitating pulmonary, but not extrapulmonary tumor initiation. PC-depleted cells demonstrated a decrease in glycolytic capacity and oxygen consumption rates and an enhanced sensitivity to oxidative stress.ConclusionsOur studies indicate that PC is specifically required for the growth of breast cancer that has disseminated to the lungs. Overall, these findings point to the potential of targeting PC for the treatment of pulmonary metastatic breast cancer.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-1008-9) contains supplementary material, which is available to authorized users.

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Inhibition of pyruvate carboxylase by 1α,25-dihydroxyvitamin D promotes oxidative stress in early breast cancer progression

Cited by 68 publications

References 31 publications

1α,25(OH)2D3 Radiosensitizes Cancer Cells by Activating the NADPH/ROS Pathway

1α,25(OH)2D3 Radiosensitizes Cancer Cells by Activating the NADPH/ROS Pathway

Pyruvate carboxylase supports the pulmonary tropism of metastatic breast cancer

Pyruvate carboxylase supports the pulmonary tropism of metastatic breast cancer

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