Integrated transcriptome and cell phenotype analysis suggest involvement of PARP1 cleavage, Hippo/Wnt, TGF-β and MAPK signaling pathways in ovarian cancer cells response to cannabis and PARP1 inhibitor treatment

Nurit Shalev, Michelle Kendall, Navin Kumar, Sudeep Tiwari, Seegehalli M. Anil, Hagit Hauschner, Savvemala G. Swamy, Adi Doron-Faingenboim, Eduard Belausov, Bruce E. Kendall, Hinanit Koltai

Research output: Contribution to journalArticlepeer-review

Abstract

Introduction: Cannabis sativa is utilized mainly for palliative care worldwide. Ovarian cancer (OC) is a lethal gynecologic cancer. A particular cannabis extract fraction ('F7′) and the Poly(ADP-Ribose) Polymerase 1 (PARP1) inhibitor niraparib act synergistically to promote OC cell apoptosis. Here we identified genetic pathways that are altered by the synergistic treatment in OC cell lines Caov3 and OVCAR3. Materials and methods: Gene expression profiles were determined by RNA sequencing and quantitative PCR. Microscopy was used to determine actin arrangement, a scratch assay to determine cell migration and flow cytometry to determine apoptosis, cell cycle and aldehyde dehydrogenase (ALDH) activity. Western blotting was used to determine protein levels. Results: Gene expression results suggested variations in gene expression between the two cell lines examined. Multiple genetic pathways, including Hippo/Wnt, TGF-β/Activin and MAPK were enriched with genes differentially expressed by niraparib and/or F7 treatments in both cell lines. Niraparib + F7 treatment led to cell cycle arrest and endoplasmic reticulum (ER) stress, inhibited cell migration, reduced the % of ALDH positive cells in the population and enhanced PARP1 cleavage. Conclusion: The synergistic effect of the niraparib + F7 may result from the treatment affecting multiple genetic pathways involving cell death and reducing mesenchymal characteristics.

Original languageEnglish
Article number1333964
JournalFrontiers in Genetics
Volume15
DOIs
StatePublished - 2024

Bibliographical note

Publisher Copyright:
Copyright © 2024 Shalev, Kendall, Kumar, Tiwari, Anil, Hauschner, Swamy, Doron-Faingenboim, Belausov, Kendall and Koltai.

Funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. Research was funded by Canna Onc Research, Santa Barbara, CA, United States.

FundersFunder number
Canna Onc Research
University of California, Santa Barbara

    Keywords

    • Hippo/Wnt pathway
    • apoptosis
    • cannabis
    • cell cycle
    • endoplasmic reticulum stress
    • mesenchymal phenotype
    • ovarian cancer
    • phytocannabinoids

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