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Novel lysophosphatidic acid receptor 6 antagonists inhibit hepatocellular carcinoma growth through affecting mitochondrial function

Abstract

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide and the commonest liver cancer. It is expected to become the third leading cause of cancer-related deaths in Western countries by 2030. Effective pharmacological approaches for HCC are still unavailable, and the currently approved systemic treatments are unsatisfactory in terms of therapeutic results, showing many side effects. Thus, searching for new effective and nontoxic molecules for HCC treatment is of paramount importance. We previously demonstrated that lysophosphatidic acid (LPA) is an important contributor to the pathogenesis of HCC and that lysophosphatidic acid receptor 6 (LPAR6) actively supports HCC tumorigenicity. Here, we screened for novel LPAR6 antagonists and found that two compounds, 4-methylene-2-octyl-5-oxotetra-hydrofuran-3-carboxylic acid (C75) and 9-xanthenylacetic acid (XAA), efficiently inhibit HCC growth, both in vitro and in vitro, without displaying toxic effects at the effective doses. We further investigated the mechanisms of action of C75 and XAA and found that these compounds determine a G1-phase cell cycle arrest, without inducing apoptosis at the effective doses. Moreover, we discovered that both molecules act on mitochondrial homeostasis, by increasing mitochondrial biogenesis and reducing mitochondrial membrane potential. Overall, our results show two newly identified LPAR6 antagonists with a concrete potential to be translated into effective and side effect–free molecules for HCC therapy.

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Acknowledgments

We are grateful to Ms. Loredana Acquaro for her precious technical support.

Funding

This work was supported by a research grant from AIRC (Italian Association for Cancer Research) to A. Mazzocca (Investigator Grant (IG) 2015 Id. 17758).

Author information

Correspondence to Antonio Mazzocca.

Ethics declarations

All animal procedures were conducted in accordance with the national and international Guidelines for the Care and Use of Laboratory and were approved by the local Institutional Animal Care and Use Committee.

Conflict of interest

The authors declare that they have no conflict of interest.

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Key messages

• Current systemic treatments for HCC are unsatisfactory with notably side effects.

• Lysophosphatidic acid receptor 6 (LPAR6) supports the tumorigenic phenotype in HCC.

• C75 and XAA, two novel LPAR6 antagonists, show anti-HCC growth properties.

• C75 and XAA affect mitochondrial function without toxicity at the effective doses.

• C75 and XAA may be translated into effective and safe molecules for HCC therapy.

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Gnocchi, D., Kapoor, S., Nitti, P. et al. Novel lysophosphatidic acid receptor 6 antagonists inhibit hepatocellular carcinoma growth through affecting mitochondrial function. J Mol Med 98, 179–191 (2020). https://doi.org/10.1007/s00109-019-01862-1

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Keywords

  • Hepatocellular carcinoma (HCC)
  • Lysophosphatidic acid receptor 6 (LPAR6)
  • Lysophosphatidic acid receptor 6 antagonists
  • Drug discovery and design
  • Drug therapy