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Targeting lysophosphatidic acid receptor with Ki16425 impedes T cell lymphoma progression through apoptosis induction, glycolysis inhibition, and activation of antitumor immune response

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Abstract

Lysophosphatidic acid (LPA) is a small phospholipid that acts as an extracellular lipid mediator. It promotes cancer progression by altering a wide array of cellular processes, including apoptosis, survival, angiogenesis, invasion, and migration through binding with its cognate receptors. Intriguingly, our previous study showed that in vitro treatment of LPA induced survival of T lymphoma cells. Hence, the present investigation was designed to investigate the antitumor potential of Ki16425, an antagonist of LPA receptors, against T cell lymphoma. Our in vitro results showed inhibition of LPA-mediated survival and metabolic activity of T lymphoma cells by Ki16425. Further, in vivo experimental findings indicated the tumor retarding potential of Ki16425 against T cell lymphoma through apoptosis induction, glycolysis inhibition, and immunoactivation. The administration of Ki16425 triggered apoptosis by down-regulating the expression of Bcl2 and up-regulating p53, Bax, cleaved caspase-3, and Cyt c expression. Further, Ki16425 suppressed glycolytic activity with concomitantly decreased expression of GLUT3 and MCT1. Moreover, we also noticed an elevated level of NO and iNOS in tumor cells after Ki16425 administration which might also be responsible for apoptosis induction and suppressed glycolysis. Additionally, we observed an increased population of total leukocytes, lymphocytes, and monocytes along with increased thymocytes count and IL-2 and IFN-γ levels. Besides, we observed amelioration of tumor-induced kidney and liver damages by Ki16425. Taken together, this is the first study that demonstrates that LPA receptors could be potential future therapeutic targets for designing promising therapeutic strategies against T cell lymphoma.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

ANOVA:

Analysis of variance

Bax:

Bcl2-associated X

Bcl2:

B-cell lymphoma 2

Cyt c:

Cytochrome c

DAPI:

4′,6-Diamidino-2-phenylindole

DL:

Dalton’s lymphoma

DMSO:

Dimethyl sulfoxide

ELISA:

Enzyme-linked Immunosorbent Assay

FBS:

Fetal bovine serum

FITC:

Fluorescein isothiocyanate

GLUT3:

Glucose transporter 3

IFN-γ:

Interferon-γ

IL-2:

Interleukin-2

iNOS:

Inducible nitric oxide synthase

LPA:

Lysophosphatidic acid

LPA1:

Lysophosphatidic acid receptor 1

LPA2:

Lysophosphatidic acid receptor 2

LPA3:

Lysophosphatidic acid receptor 3

MCT1:

Monocarboxylate transporter 1

MTT:

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

NO:

Nitric oxide

PBS:

Phosphate-buffered saline

RPMI:

Roswell park memorial institute

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 SERB, New Delhi. The authors thank the Interdisciplinary School of Life Science (ISLS), BHU, Varanasi for fluorescence microscopy and gel documentation system. The authors are highly thankful to Prof. Sukh Mahendra Singh (School of Biotechnology, Institute of Science, Banaras Hindu University) for his valuable inputs and for providing his lab facility for ELISA. Funding from the Department of Science & Technology, New Delhi, India, in the form of the Early Career Research Award (ECR/2016/001117) is highly acknowledged. Financial support of the Institute of Eminence (IoE) (6031) from Banaras Hindu University, India, is highly acknowledged. We also acknowledge the UGC-CAS and DST-FIST program to the Department of Zoology, Banaras Hindu University, India.

Funding

This work was supported by SERB, New Delhi, India [Project no. ECR/2016/001117].

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

    Vishal Kumar Gupta & Ajay Kumar

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  1. Vishal Kumar Gupta
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The experiments of this study were designed by AK and VKG. VKG has performed the experiments. AK and VKG analyzed the data. The manuscript was written by AK and VKG. AK and VKG read and approved the final version of the manuscript.

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Correspondence to Ajay Kumar.

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Gupta, V.K., Kumar, A. Targeting lysophosphatidic acid receptor with Ki16425 impedes T cell lymphoma progression through apoptosis induction, glycolysis inhibition, and activation of antitumor immune response. Apoptosis 27, 382–400 (2022). https://doi.org/10.1007/s10495-022-01723-2

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