HOLOTHURIA SCABRA METHANOL EXTRACT INHIBITS CANCER GROWTH THROUGH TGF-β/PI3K/PTEN SIGNALING PATHWAY IN BREAST CANCER MICE MODEL

Authors

  • HANA RATNAWATI Faculty of Medicine, Maranatha Christian University, Bandung, Indonesia
  • TERESA LILIANA WARGASETIA Faculty of Medicine, Maranatha Christian University, Bandung, Indonesia
  • LARISSA LARISSA Faculty of Medicine, Maranatha Christian University, Bandung, Indonesia
  • LIANA ALVITRI Faculty of Medicine, Maranatha Christian University, Bandung, Indonesia
  • KEANE BRYANT Faculty of Medicine, Maranatha Christian University, Bandung, Indonesia

DOI:

https://doi.org/10.15407/exp-oncology.2024.01.022

Keywords:

anticancer activity, breast cancer, Holothuria scabra, TGF-β/PIK3CA, PTEN

Abstract

Background. Molecules and cytokines can be targeted in cancer therapy. Transforming growth factor-beta (TGF-β) is a cytokine that acts on protein kinase receptors in the plasma membrane. The signaling pathway of TGF-β can trigger the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway, a signal transduction pathway important in cancer growth and development. However, this PI3K/AKT cascade can be inhibited by phosphatase and tensin homolog (PTEN) tumor suppressor genes. Aim. To determine the inhibitory effect of Holothuria scabra methanol extract (HSE) on breast cancer growth through the TGF-β/PI3K pathways and PTEN tumor suppressor gene on a breast cancer (BC) mice model. Materials and Methods. Female C57BL6 mice were subcutaneously injected with carcinogen DMBA 1 mg/kg body weight (BW) and fed a high-fat diet (HFD). Mice were randomly divided into five groups (n = 6): negative control (NC) administered with a standard diet, positive control (PC) administered with DMBA and HFD, and three treatment groups (T1, T2, and T3) treated with HSE doses of 0.33, 0.66, and 0.99 g/kg BW for 12 weeks. TGF-β concentration in the blood serum of mice was assessed by ELISA and the PIK3CA and PTEN gene expression by qRT-PCR. Results. The treatment with HSE resulted in a significant decrease in TGF-β concentrations in the blood sera of treatment groups T1 (35.31 ± 17.33), T2 (43.31 ± 17.42), and T3 (48.67 ± 20.94) pg/mL compared to the PC group (162.09 ± 11.60) pg/mL (p < 0.001). However, only HSE at a dose of 0.99 g/kg BW decreased the PIK3CA gene expression (p = 0.026), and at a dose of 0.66 g/kg BW increased the PTEN expression up to 4.93-fold. Conclusion. HSE is capable of inhibiting the TGF-β/PIK3CA pathway and increasing the PTEN gene expression.

References

Calone I, Souchelnytskyi S. Inhibition of TGFβ signaling and its implications in anticancer treatments. Exp Oncol. 2012;34(1):9-16.

Khoshakhlagh M, Soleimani A, Binabaj MM, et al. Therapeutic potential of pharmacological TGF-β signaling pathway inhibitors in the pathogenesis of breast cancer. Biochem Pharmacol. 2019;164:17-22. https://doi.org/10.1016/j.bcp.2019.03.031

Fujio K, Komai T, Inoue M, et al. Revisiting the regulatory roles of the TGF-β family of cytokines. Autoimmun Rev. 2016;15(9):917-922. https://doi.org/10.1016/j.autrev.2016.07.007

Ghayad S, Cohen P. Inhibitors of the PI3K/Akt/mTOR Pathway: new hope for breast cancer patients. Recent Pat Anticancer Drug Discov. 2010;5(1):29-57. https://doi.org/10.2174/157489210789702208

Crowder RJ, Phommaly C, Tao Y, et al. PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer. Cancer Res. 2009;69(9):3955-3962. https://doi.org/10.1158/0008-5472

Luongo F, Colonna F, Calapà F, et al. PTEN tumor-suppressor: the dam of stemness in cancer. Cancers. 2019;11(8):1076. https://doi.org/10.3390/cancers11081076

Pangestuti R, Ari Z. Benefit effects of functional sea cucumbers. J Tradit Complement Med. 2018;8(3):341-351. https://doi.org/10.1016/j.jtcme.2017.06.007

Wargasetia TL, Ratnawati H, Widodo N. Anticancer potential of Holothurin A, Holothurin B, and Holothurin B3 from the sea cucumber Holothuria scabra. AIP Conf Proc. 2020:2231. https://doi.org/10.1063/5.0002552

Hoang L, Le Thi V, Tran Thi Hong H, et al. Triterpene glycosides from the Vietnamese sea cucumber Holothuria edulis. Nat Prod Res. 2020;34(8):1061-1067. https://doi.org/10.1080/14786419.2018.1548451

Cranford TL, Velázquez KT, Enos RT, et al. Effects of high fat diet-induced obesity on mammary tumorigenesis in the PyMT/MMTV murine model. Cancer Biol Ther. 2019;3;20(4):487–496. doi:10.1080/15384047.2018.1537574

Kinoshita Y, Yoshioka M, Emoto Y, et al. Dietary effect of mead acid on DMBA-induced breast cancer in female Sprague–Dawley rats. Int J Funct Nutr. 2020;1(2):1. https://doi.org/10.3892/ijfn.2020.7

Simpson JF, Gray R, Dressler LG, et al. Prognostic value of histologic grade and proliferative activity in axillary node–positive breast cancer: results from the Eastern Cooperative Oncology Group Companion Study, EST 4189. J Clin Oncol. 2000;18(10):2059-2069. https://doi.org/10.1200/JCO.2000.18.10.2059

Purcell S, Samyn Y, Conand C. Commercially important sea cucumbers of the world. 2012;6:150 p. https://doi.org/10.4060/cc5230en

Li M, Zhang W, Yang L, et al. The mechanism of Xiaoyao San in the treatment of ovarian cancer by network pharmacology and the effect of stigmasterol on the PI3K/Akt pathway. Dis Markers. 2021:4304507. https://doi.org/10.1155/2021/4304507

Wargasetia TL, Ratnawati H, Liana LK, et al. Holothuria scabra extract improves histopathological features and inhibits cancer growth through IL-6 and NF κ B signaling pathways in carcinoma mammae mice model. Res J Pharmacogn. 2024;11(2):1-9. https://doi.org/10.22127/rjp.2023.417833.2233

Xie F, Ling L, Van Dam H, et al. TGF-beta signaling in cancer metastasis. Acta Biochim Biophys Sin (Shanghai). 2018;50(1):121-132. https://doi.org/10.1093/abbs/gmx123

Gillespie C, Quarshie A, Penichet M, et al. Potential role of leptin signaling in DMBA induced mammary tumors by non-responsive C57BL/6J Mice Fed a high-fat diet. J Carcinog Mutagen. 2012;3(132):20-23. https://doi.org/10.4172/2157-2518.1000132

Rosdianto AM, Kurniawan A, Gunadi JW, et al. DMBA-induced modulate estrogen receptors α and β breast cancer’s animal model. Maj Kedokt Bandung. 2022;54(1):37-42. https://doi.org/10.15395/mkb.v54n1.2479

Abba MC, Zhong Y, Lee J, et al. DMBA induced mouse mammary tumors display high incidence of activating Pik3caH1047 and loss of function Pten mutations. Oncotarget. 2016;7(39):64289-64299. https://doi.org/10.18632/oncotarget.11733

Wargasetia TL, Ratnawati H, Widodo N. Anticancer potential of Holothurin A, Holothurin B, and Holothurin B3 from the sea cucumber Holothuria scabra. In: AIP Conf Proc. 2020;2231:040084. https://doi.org/10.1063/5.0002552

Khotimchenko Y. Pharmacological potential of sea cucumbers. Int J Mol Sci. 2018;19(5):1342. https://doi.org/10.3390/ijms19051342

Batlle E, Massagué J. Transforming growth factor-β Signaling in immunity and cancer. Immunity. 2019;50(4):924-940. https://doi.org/10.1016/j.immuni.2019.03.024

Chen Y, Di C, Zhang X, et al. Transforming growth factor β signaling pathway: A promising therapeutic target for cancer. J Cell Physiol. 2020;235(3):1903-1914. https://doi.org/10.1002/jcp.29108

Song K, Wang H, Krebs TL. Novel roles of Akt and mTOR in suppressing TGF-β/ALK5-mediated Smad3 activation. EMBO J. 2006;25(1):58-69. https://doi.org/10.1038/sj.emboj.7600917

Zhao M, Mishra L, Deng CX. The role of TGF-β/SMAD4 signaling in cancer. Int J Biol Sci. 2018;14(2):111-123. https://doi.org/10.7150/ijbs.23230

Lu Z, Sun N, Dong L, et al. Production of bioactive peptides from sea cucumber and its potential health benefits: a comprehensive review. J Agric Food Chem. 2022;70(25):7607-7625. https://doi.org/10.1021/acs.jafc.2c02696

Wargasetia TL, Ratnawati H, Widodo N, et al. Bioinformatics study of sea cucumber peptides as antibreast cancer through inhibiting the activity of overexpressed protein (EGFR, PI3K, AKT1, and CDK4). Cancer Informatics. 2021;20:1-11. https://doi.org/10.1177/11769351211031864

Assinder SJ, Dong Q, Kovacevic Z, et al. The TGF-β, PI3K/Akt and PTEN pathways: established and proposed biochemical integration in prostate cancer. Biochem J. 2009;417(2):411-421. https://doi.org/10.1042/BJ20081610

Downloads

Published

31.05.2024

How to Cite

RATNAWATI, H., WARGASETIA, T. L., LARISSA, L., ALVITRI, L., & BRYANT, K. (2024). HOLOTHURIA SCABRA METHANOL EXTRACT INHIBITS CANCER GROWTH THROUGH TGF-β/PI3K/PTEN SIGNALING PATHWAY IN BREAST CANCER MICE MODEL. Experimental Oncology, 46(1), 22–29. https://doi.org/10.15407/exp-oncology.2024.01.022

Issue

Section

Original contributions