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Lysophosphatidic acid promotes survival of T lymphoma cells by altering apoptosis and glucose metabolism

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Abstract

Lysophosphatidic acid (LPA) is a bioactive lipid, which plays an indispensable role in various physiological and pathological processes. Moreover, an elevated level of LPA has been observed in malignancies of different origins and implicated in their progression via modulation of proliferation, apoptosis, invasion and metastasis. Interestingly, few recent reports suggest a pivotal role of LPA-modulated metabolism in oncogenesis of ovarian cancer. However, little is understood regarding the role of LPA in the development and progression of T cell malignancies, which are considered as one of the most challenging neoplasms for clinical management. Additionally, mechanisms underlying the LPA-dependent modulation of glucose metabolism in T cell lymphoma are also not known. Therefore, the present study was undertaken to explore the role of LPA-altered apoptosis and glucose metabolism on the survival of T lymphoma cells. Observations of this investigation suggest that LPA supports survival of T lymphoma cells via altering apoptosis and glucose metabolism through changing the level of reactive species, namely nitric oxide and reactive oxygen species along with expression of various survival and glucose metabolism regulatory molecules, including hypoxia-inducible factor 1-alpha, p53, Bcl2, and glucose transporter 3, hexokinase II, pyruvate kinase muscle isozyme 2, monocarboxylate transporter 1, pyruvate dehydrogenase kinase 1. Taken together‚ the results of the present investigation decipher the novel mechanisms of LPA-mediated survival of T lymphoma cells via modulation of apoptosis and glucose metabolism.

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Abbreviations

ANOVA:

Analysis of variance

BCIP/NBT:

5-Bromo-4-chloro-3′-indolyphosphate/nitro-blue tetrazolium

DCFDA:

2′,7′-Dichlorofluorescin diacetate

DL cells:

Dalton’s lymphoma cells

EDTA:

Ethylenediaminetetraacetic acid

FBS:

Fetal bovine serum

FITC:

Fluorescein isothiocyanate

GLUT 3:

Glucose transporter 3

HIF1-α:

Hypoxia-inducible factor 1-alpha

HKII:

HexokinaseII

LPA:

Lysophosphatidic acid

MCT1:

Monocarboxylate transporter 1

MTT:

3-(4,5-Dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide

NO:

Nitric oxide

PBS:

Phosphate-buffered saline

PDK1:

Pyruvate dehydrogenase kinase 1

PI:

Propidium iodide

PIPES:

Piperazine-N,N′-bis(2-ethanesulfonic acid)

ROS:

Reactive oxygen species

RPMI:

Roswell park memorial institute medium

RT-PCR:

Reverse-transcription polymerase chain reaction

SDS:

Sodium dodecyl sulfate

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Acknowledgements

The fellowship to Vishal Kumar Gupta is supported by a project (ECR/2016/001117) sanctioned by Department of Science & Technology, New Delhi. We thankfully acknowledge fellowship support to Pradip Kumar Jaiswara [Award No. 1002/(SC)(CSIR-UGC NET DEC. 2016]; Shiv Govind Rawat [Award No. 09/013(0772/2018-EMR-I)] from Council of Scientific and Industrial Research (CSIR), New Delhi; Pratishtha Sonker [Award No. F117.1/201516/ RGNF201517SCUTT4822/(SAIII/Website)] from University Grants Commission (UGC), New Delhi; Rajan Kumar Tiwari [Award No. R/Dev/IX-Sch.(SRF-JRF-CAS-Zoology)/75159] from University Grants Commission-Career Advancement Scheme (UGC-CAS). Funding from University Grants Commission and Department of Science & Technology, New Delhi, India, in the form of UGC-Start-Up Research (F. No. 30-370/2017 (BSR)) and Early Career Research Award (ECR/2016/001117) is highly acknowledged. Financial support from Interdisciplinary School of Life Science (ISLS) and University Grants Commission-Universities with Potential for Excellence (UGC-UPE), Banaras Hindu University is also acknowledged. We also acknowledge UGC-CAS and DST-FIST program to the Department of Zoology, Banaras Hindu University, India. We acknowledge the support of Dr. S.D. Singh for the measurement of lactate level. We thank Prof. Sukh Mahendra Singh, School of Biotechnology, Banaras Hindu University, Varanasi, India, for providing few instrumentation facilities of his laboratory and his valuable suggestions.

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  1. Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, 221005, India

    Vishal Kumar Gupta, Pradip Kumar Jaiswara, Pratishtha Sonker, Shiv Govind Rawat, Rajan Kumar Tiwari & Ajay Kumar

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The research work presented in this manuscript is part of the Ph.D. thesis of VKG. The experiments of this investigation were designed by AK and VKG. VKG has performed the entire experiment. The manuscript was written by AK and VKG. VKG, PKJ, PS, SGR, and RKT prepared reagents and analyzed the data. All authors read and approved the final version of the manuscript.

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Correspondence to Ajay Kumar.

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Gupta, V.K., Jaiswara, P.K., Sonker, P. et al. Lysophosphatidic acid promotes survival of T lymphoma cells by altering apoptosis and glucose metabolism. Apoptosis 25, 135–150 (2020). https://doi.org/10.1007/s10495-019-01585-1

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