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VD3 and LXR agonist (T0901317) combination demonstrated greater potency in inhibiting cholesterol accumulation and inducing apoptosis via ABCA1-CHOP-BCL-2 cascade in MCF-7 breast cancer cells

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Abstract

Obesity is associated with hypercholesterolemia and is a global epidemic. Epidemiological and animal studies revealed cholesterol is an essential regulator of estrogen receptor positive (ER+) breast cancer progression while inhibition of cholesterol accumulation was found to prevent breast tumor growth. Individually, vitamin D and LXR agonist T0901317 showed anticancer properties. The present study investigated the effects of vitamin D3 (VD3, calcitriol), LXR agonist (T0901317) and a combination of VD3 + T0901317 on cholesterol metabolism and cancer progression in ER+ breast cancer (MCF-7) cells. VD3 or T0901317 alone reduced cholesterol accumulation significantly in MCF-7 cells concomitant with an induction of ABCA1 protein and gene expression compared to the control treatment. Most importantly, VD3 + T0901317 combination showed higher effects in reducing cholesterol levels and increasing ABCA1 protein and gene expression compared to individual treatments. Importantly, VD3 + T0901317 combination showed higher effects in increasing apoptosis as measured by annexin apoptosis assay, cell viability and was associated with induction of CHOP protein and gene expression. Additionally, the VD3 + T0901317 exerted higher effects in reducing antiapoptotic BCL-2 while increased pro-apoptotic BAX gene expression compared to the individual treatments. The present results suggest that VD3 and T0901317 combination may have an important therapeutic application to prevent obesity and hyperlipidemia mediated ER+ breast cancer progression.

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Abbreviations

LXR:

Liver X receptor

ER+:

Estrogen receptor positive

ABCA1:

ATP binding cassette subfamily A member 1

27-HC:

27-Hydroxycholesterol

CHOP:

CCAAT/enhancer-binding protein (C/EBP) homologous protein

VD3 :

Vitamin D3

VDR:

Vitamin D receptor

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Acknowledgements

MTM was supported by Doctoral Dissertation Completion Fellowship and Presidential NRUF Research Fellowship provided by Texas Tech University. CP was supported by Center for the Integration of STEM Education & Research (CISER), Texas Tech University. FH was partially supported by Texas Tech University President's Distinguished Chair Fund.

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Author notes

  1. Maliha T. Munir and Christopher Ponce have contributed equally to this work.

Authors and Affiliations

  1. Nutritional Sciences, Texas Tech University, Lubbock, TX, USA

    Maliha T. Munir, Hazera Binte Sufian & Lauren S. Gollahon

  2. Mathematics, Texas Tech University, Lubbock, TX, USA

    Christopher Ponce

  3. Texas Tech Health Sciences Center, Lubbock, TX, USA

    Julianna M. Santos

  4. Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Sultanate of Oman

    Ahmed Al-Harrasi & Shaikh Mizanoor Rahman

  5. Department of Biological Sciences, Texas Tech University, Lubbock, TX, USA

    Lauren S. Gollahon

  6. Mechanical Engineering, Texas Tech University, Lubbock, TX, USA

    Fazle Hussain

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  1. Maliha T. Munir
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  2. Christopher Ponce
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  3. Julianna M. Santos
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  4. Hazera Binte Sufian
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SMR designed and supervised the project. MTM and CP performed experiments and analyzed data. All authors took part in data interpretation and manuscript preparation. The final manuscript was reviewed and approved by all authors.

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Correspondence to Shaikh Mizanoor Rahman.

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Munir, M.T., Ponce, C., Santos, J.M. et al. VD3 and LXR agonist (T0901317) combination demonstrated greater potency in inhibiting cholesterol accumulation and inducing apoptosis via ABCA1-CHOP-BCL-2 cascade in MCF-7 breast cancer cells. Mol Biol Rep 47, 7771–7782 (2020). https://doi.org/10.1007/s11033-020-05854-0

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