Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Jun;27(5-6):382-400.
doi: 10.1007/s10495-022-01723-2. Epub 2022 Apr 2.

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

Vishal Kumar Gupta  1 , Ajay Kumar  2
Affiliations

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

Vishal Kumar Gupta et al. Apoptosis. 2022 Jun.

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.

Keywords: Antitumor immune response; Apoptosis; Glucose metabolism; Ki16425; LPA; T cell lymphoma.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

References

    1. Abdelbaset-Ismail A, Cymer M, Borkowska-Rzeszotek S et al (2019) Bioactive phospholipids enhance migration and adhesion of human leukemic cells by inhibiting heme oxygenase 1 (HO-1) and inducible nitric oxygenase synthase (iNOS) in a p38 MAPK-dependent manner. Stem Cell Rev Rep 15:139–154 - PubMed - DOI
    1. Bae GH, Lee SK, Kim HS, Lee M, Lee HY, Bae YS (2017) Lysophosphatidic acid protects against acetaminophen-induced acute liver injury. Exp Mol Med 49:e407 - PubMed - PMC - DOI
    1. Kang S, Han J, Song SY et al (2015) Lysophosphatidic acid increases the proliferation and migration of adiposederived stem cells via the generation of reactive oxygen species. Mol Med Rep 12:5203–5210 - PubMed - DOI
    1. Ray R, Rai V (2017) Lysophosphatidic acid converts monocytes into macrophages in both mice and humans. Blood 129:1177–1183 - PubMed - DOI
    1. Choi JW, Herr DR, Noguchi K et al (2010) LPA receptors: subtypes and biological actions. Annu Rev Pharmacol Toxicol 50:157–186 - PubMed - DOI

Publication types

Substances

LinkOut - more resources