Pseudolaric acid B induces apoptosis associated with the mitochondrial and PI3K/AKT/mTOR pathways in triple‑negative breast cancer

Yang,Ke; Wang,Jun-Qi; Li,Kai; Chen,Su-Ning; Yu,Fei

doi:10.3892/or.2023.8630

November-2023 Volume 50 Issue 5

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

November-2023 Volume 50 Issue 5

Full Size Image

Article Open Access

Pseudolaric acid B induces apoptosis associated with the mitochondrial and PI3K/AKT/mTOR pathways in triple‑negative breast cancer

Authors:
- Ke Yang
- Jun-Qi Wang
- Kai Li
- Su-Ning Chen
- Fei Yu
View Affiliations / Copyright

Affiliations: Department of Traditional Chinese Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China, Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China, Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China

Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Article Number: 193
|
Published online on: September 14, 2023

https://doi.org/10.3892/or.2023.8630
Expand metrics +

Abstract

Pseudolaric acid B (PAB), a diterpene acid isolated from the root bark of Pseudolarix kaempferi, has been shown to exert strong antitumor properties. The aim of the present study was to investigate the mechanisms underlying the proposed antitumor properties of PAB in the triple‑negative breast cancer cells, MDA‑MB‑231. The cell processes evaluated included cell proliferation by Cell Counting Kit‑8 assay, colony formation and EdU assay, apoptosis by Annexin V‑FITC/PI apoptosis assay, cell migration by Transwell migration assay and invasion by Transwell invasion assay. PAB significantly inhibited the proliferation of MDA‑MB‑231 cells through a mechanism that was considered to be associated with cell cycle arrest at the G₂/M phase. There was decreased protein expression levels of CDK1 and cyclin B1 and increased protein expression levels of p53 and p21. However, there were no well‑defined inhibitory effects on the normal breast cell line MCF10A. PAB also triggered apoptosis in a concentration‑dependent manner through the mitochondrial apoptosis pathway. It caused collapse of mitochondrial membrane potential, accumulation of reactive oxygen species and release of cytochrome c, as well as upregulation of cleaved caspase‑3, cleaved caspase‑9, cleaved PARP and Bax, and downregulation of Bcl‑2 and Bcl‑xl. The migration and invasion ability of MDA‑MB‑231 cells were inhibited by decreasing the expression levels of the epithelial‑mesenchymal transition‑related markers N‑cadherin and vimentin and increasing the expression of E‑cadherin. Moreover, the expression levels of PI3K (p110β), phosphorylated (p)‑AKT (ser⁴⁷³) and p‑mTOR (ser²⁴⁴⁸) were downregulated and LY294002, a PI3K inhibitor, could interact additively with PAB to induce apoptosis of MDA‑MB‑231 cells. Overall, the present results demonstrated that PAB induced apoptosis via mitochondrial apoptosis and the PI3K/AKT/mTOR pathway in triple‑negative breast cancer. It also inhibited cellular proliferation, migration and invasion, suggesting that PAB may be a useful phytomedicine for the treatment of triple‑negative breast cancer.

View Figures

View References

1	Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021. View Article : Google Scholar : PubMed/NCBI
2	Yin L, Duan JJ, Bian XW and Yu SC: Triple-negative breast cancer molecular subtyping and treatment progress. Breast Cancer Res. 22:612020. View Article : Google Scholar : PubMed/NCBI
3	Garrido-Castro AC, Lin NU and Polyak K: Insights into molecular classifications of triple-negative breast cancer: Improving patient selection for treatment. Cancer Discov. 9:176–198. 2019. View Article : Google Scholar : PubMed/NCBI
4	Lu J, Guan H, Wu D, Hu Z, Zhang H, Jiang H, Yu J, Zeng K, Li H, Zhang H, et al: Pseudolaric acid B ameliorates synovial inflammation and vessel formation by stabilizing PPARγ to inhibit NF-κB signalling pathway. J Cell Mol Med. 25:6664–6678. 2021. View Article : Google Scholar : PubMed/NCBI
5	Li Z, Yin H, Chen W, Jiang C, Hu J, Xue Y, Yao D, Peng Y and Hu X: Synergistic effect of pseudolaric Acid B with fluconazole against resistant isolates and biofilm of candida tropicalis. Infect Drug Resist. 13:2733–2743. 2020. View Article : Google Scholar : PubMed/NCBI
6	Miao ZH, Feng JM and Ding J: Newly discovered angiogenesis inhibitors and their mechanisms of action. Acta Pharmacol Sin. 33:1103–11. 2012. View Article : Google Scholar : PubMed/NCBI
7	Wei SF, He DH, Zhang SB, Lu Y, Ye X, Fan XZ, Wang H, Wang Q and Liu YQ: Identification of pseudolaric acid B as a novel Hedgehog pathway inhibitor in medulloblastoma. Biochem Pharmacol. 190:1145932021. View Article : Google Scholar : PubMed/NCBI
8	Mafu S, Karunanithi PS, Palazzo TA, Harrod BL, Rodriguez SM, Mollhoff IN, O'Brien TE, Tong S, Fiehn O, Tantillo DJ, et al: Biosynthesis of the microtubule-destabilizing diterpene pseudolaric acid B from golden larch involves an unusual diterpene synthase. Proc Natl Acad Sci USA. 114:974–979. 2017. View Article : Google Scholar : PubMed/NCBI
9	Zhang H, Li JC, Luo H, Zhao L, Zhang ZD and Shen XF: Pseudolaric acid B exhibits anti-cancer activity on human hepatocellular carcinoma through inhibition of multiple carcinogenic signaling pathways. Phytomedicine. 59:1527592019. View Article : Google Scholar : PubMed/NCBI
10	Wang D, Xin Y, Tian Y, Li W, Sun D and Yang Y: Pseudolaric acid B inhibits gastric cancer cell metastasis in vitro and in haematogenous dissemination model through PI3K/AKT, ERK1/2 and mitochondria-mediated apoptosis pathways. Exp Cell Res. 352:34–44. 2017. View Article : Google Scholar : PubMed/NCBI
11	Yao GD, Yang J, Li XX, Song XY, Hayashi T, Tashiro SI, Onodera S, Song SJ and Ikejima T: Blocking the utilization of glucose induces the switch from senescence to apoptosis in pseudolaric acid B-treated human lung cancer cells in vitro. Acta Pharmacol Sin. 38:1401–1411. 2017. View Article : Google Scholar : PubMed/NCBI
12	Jiang L, Wen C, He Q, Sun Y, Wang J, Lan X, Rohondia S, Dou QP, Shi X and Liu J: Pseudolaric acid B induces mitotic arrest and apoptosis in both imatinib-sensitive and -resistant chronic myeloid leukaemia cells. Eur J Pharmacol. 876:1730642020. View Article : Google Scholar : PubMed/NCBI
13	Hanahan D: Hallmarks of cancer: New dimensions. Cancer Discov. 12:31–46. 2022. View Article : Google Scholar : PubMed/NCBI
14	Jeong SY and Seol DW: The role of mitochondria in apoptosis. BMB Rep. 41:11–22. 2008. View Article : Google Scholar : PubMed/NCBI
15	Carneiro BA and El-Deiry WS: Targeting apoptosis in cancer therapy. Nat Rev Clin Oncol. 17:395–417. 2020. View Article : Google Scholar : PubMed/NCBI
16	Guan D, Li C, Lv X and Yang Y: Pseudolaric acid B inhibits PAX2 expression through Wnt signaling and induces BAX expression, therefore promoting apoptosis in HeLa cervical cancer cells. J Gynecol Oncol. 30:e772019. View Article : Google Scholar : PubMed/NCBI
17	Choi SJ, Ahn CH, Yang IH, Jin B, Lee WW, Kim JH, Ahn MH, Swarup N, Hong KO, Shin JA, et al: Pseudolaric Acid B induces growth inhibition and caspase-dependent apoptosis on head and neck cancer cell lines through death receptor 5. Molecules. 24:37152019. View Article : Google Scholar : PubMed/NCBI
18	Wen C, Chen J, Zhang D, Wang H, Che J, Qin Q, He L, Cai Z, Lin M, Lou Q, et al: Pseudolaric acid B induces mitotic arrest and apoptosis in both 5-fluorouracil-sensitive and -resistant colorectal cancer cells. Cancer Lett. 383:295–308. 2016. View Article : Google Scholar : PubMed/NCBI
19	Polivka J Jr and Janku F: Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol Ther. 142:164–175. 2014. View Article : Google Scholar : PubMed/NCBI
20	Bartholomeusz C and Gonzalez-Angulo AM: Targeting the PI3K signaling pathway in cancer therapy. Expert Opin Ther Targets. 16:121–130. 2012. View Article : Google Scholar : PubMed/NCBI
21	Claerhout S, Decraene D, Van Laethem A, Van Kelst S, Agostinis P and Garmyn M: AKT delays the early-activated apoptotic pathway in UVB-irradiated keratinocytes via BAD translocation. J Invest Dermatol. 127:429–438. 2007. View Article : Google Scholar : PubMed/NCBI
22	Quan JH, Cha GH, Zhou W, Chu JQ, Nishikawa Y and Lee YH: Involvement of PI 3 kinase/Akt-dependent Bad phosphorylation in Toxoplasma gondii-mediated inhibition of host cell apoptosis. Exp Parasitol. 133:462–471. 2013. View Article : Google Scholar : PubMed/NCBI
23	Fulda S: Synthetic lethality by co-targeting mitochondrial apoptosis and PI3K/Akt/mTOR signaling. Mitochondrion. 19:85–87. 2014. View Article : Google Scholar : PubMed/NCBI
24	Zuo A, Zhao P, Zheng Y, Hua H and Wang X: Tripterine inhibits proliferation, migration and invasion of breast cancer MDA-MB-231 cells by up-regulating microRNA-15a. Biol Chem. 400:1069–1078. 2019. View Article : Google Scholar : PubMed/NCBI
25	Yang W, Feng B, Meng Y, Wang J, Geng B, Cui Q, Zhang H, Yang Y and Yang J: FAM3C-YY1 axis is essential for TGFβ-promoted proliferation and migration of human breast cancer MDA-MB-231 cells via the activation of HSF1. J Cell Mol Med. 23:3464–3475. 2019. View Article : Google Scholar : PubMed/NCBI
26	Lou C, Xu X, Chen Y and Zhao H: Alisol A suppresses proliferation, migration, and invasion in human breast cancer MDA-MB-231 cells. Molecules. 24:36512019. View Article : Google Scholar : PubMed/NCBI
27	Kheirandish-Rostami M, Roudkenar MH, Jahanian-Najafabadi A, Tomita K, Kuwahara Y, Sato T and Roushandeh AM: Mitochondrial characteristics contribute to proliferation and migration potency of MDA-MB-231 cancer cells and their response to cisplatin treatment. Life Sci. 244:1173392020. View Article : Google Scholar : PubMed/NCBI
28	Tohkayomatee R, Reabroi S, Tungmunnithum D, Parichatikanond W and Pinthong D: Andrographolide exhibits anticancer activity against breast cancer cells (MCF-7 and MDA-MB-231 cells) through suppressing cell proliferation and inducing cell apoptosis via inactivation of ER-α receptor and PI3K/AKT/mTOR signaling. Molecules. 27:35442022. View Article : Google Scholar : PubMed/NCBI
29	Yu B, Yue DM, Shu LH, Li NJ and Wang JH: Pseudolaric acid B induces caspase-dependent cell death in human ovarian cancer cells. Oncol Rep. 31:849–857. 2014. View Article : Google Scholar : PubMed/NCBI
30	Wang D, Tian Y, Feng W, Zhao L, Zhao M, Liu J and Wang Q: Pseudolaric acid B induces endometrial cancer Ishikawa cell apoptosis and inhibits metastasis through AKT-GSK-3β and ERK1/2 signaling pathways. Anticancer Drugs. 28:603–612. 2017. View Article : Google Scholar : PubMed/NCBI
31	Li X, Zhao X, Song W, Tian Z, Yang L, Niu Q, Zhang Q, Xie M, Zhou B, Xu Y, et al: Pseudolaric Acid B inhibits proliferation, invasion and Epithelial-to-mesenchymal transition in human pancreatic cancer cell. Yonsei Med J. 59:20–27. 2018. View Article : Google Scholar : PubMed/NCBI
32	Matthews HK, Bertoli C and de Bruin RAM: Cell cycle control in cancer. Nat Rev Mol Cell Biol. 23:74–88. 2022. View Article : Google Scholar : PubMed/NCBI
33	Dong C, Wen S, Zhao S, Sun S, Zhao S, Dong W, Han P, Chen Q, Gong T, Chen W, et al: Salidroside inhibits reactive astrogliosis and glial scar formation in late cerebral ischemia via the Akt/GSK-3β pathway. Neurochem Res. 46:755–769. 2021. View Article : Google Scholar : PubMed/NCBI
34	Bao Y, Wu X, Jin X, Kanematsu A, Nojima M, Kakehi Y and Yamamoto S: Apigenin inhibits renal cell carcinoma cell proliferation through G2/M phase cell cycle arrest. Oncol Rep. 47:602022. View Article : Google Scholar : PubMed/NCBI
35	He YC, He L, Khoshaba R, Lu FG, Cai C, Zhou FL, Liao DF and Cao D: Curcumin nicotinate selectively induces cancer cell apoptosis and cycle arrest through a P53-mediated mechanism. Molecules. 24:41792019. View Article : Google Scholar : PubMed/NCBI
36	Ma K, Wang K, Zhou Y, Liu N, Guo W, Qi J, Hu Z, Su S, Tang P and Zhou X: Purified vitexin compound 1 serves as a promising antineoplastic agent in ovarian cancer. Front Oncol. 11:7347082021. View Article : Google Scholar : PubMed/NCBI
37	Xie B, Wang S, Jiang N and Li JJ: Cyclin B1/CDK1-regulated mitochondrial bioenergetics in cell cycle progression and tumor resistance. Cancer Lett. 443:56–66. 2019. View Article : Google Scholar : PubMed/NCBI
38	Fischer M, Quaas M, Steiner L and Engeland K: The p53-p21-DREAM-CDE/CHR pathway regulates G2/M cell cycle genes. Nucleic Acids Res. 44:164–174. 2016. View Article : Google Scholar : PubMed/NCBI
39	Engeland K: Cell cycle arrest through indirect transcriptional repression by p53: I have a DREAM. Cell Death Differ. 25:114–132. 2018. View Article : Google Scholar : PubMed/NCBI
40	Abate M, Festa A, Falco M, Lombardi A, Luce A, Grimaldi A, Zappavigna S, Sperlongano P, Irace C, Caraglia M and Misso G: Mitochondria as playmakers of apoptosis, autophagy and senescence. Semin Cell Dev Biol. 98:139–153. 2020. View Article : Google Scholar : PubMed/NCBI
41	Yang Y, Karakhanova S, Hartwig W, D'Haese JG, Philippov PP, Werner J and Bazhin AV: Mitochondria and mitochondrial ROS in cancer: Novel targets for anticancer therapy. J Cell Physiol. 231:2570–2581. 2016. View Article : Google Scholar : PubMed/NCBI
42	Cao K and Tait SWG: Apoptosis and cancer: Force awakens, phantom menace, or both? Int Rev Cell Mol Biol. 337:135–152. 2018. View Article : Google Scholar : PubMed/NCBI
43	Deepak KGK, Vempati R, Nagaraju GP, Dasari VR, S N, Rao DN and Malla RR: Tumor microenvironment: Challenges and opportunities in targeting metastasis of triple negative breast cancer. Pharmacol Res. 153:1046832020. View Article : Google Scholar : PubMed/NCBI
44	Hosonaga M, Saya H and Arima Y: Molecular and cellular mechanisms underlying brain metastasis of breast cancer. Cancer Metastasis Rev. 39:711–720. 2020. View Article : Google Scholar : PubMed/NCBI
45	Rakha EA and Chan S: Metastatic triple-negative breast cancer. Clin Oncol (R Coll Radiol). 23:587–600. 2011. View Article : Google Scholar : PubMed/NCBI
46	Pastushenko I and Blanpain C: EMT transition states during tumor progression and metastasis. Trends Cell Biol. 29:212–226. 2019. View Article : Google Scholar : PubMed/NCBI
47	Zhang Y and Weinberg RA: Epithelial-to-mesenchymal transition in cancer: Complexity and opportunities. Front Med. 12:361–373. 2018. View Article : Google Scholar : PubMed/NCBI
48	Aiello NM and Kang Y: Context-dependent EMT programs in cancer metastasis. J Exp Med. 216:1016–1026. 2019. View Article : Google Scholar : PubMed/NCBI
49	Yu J, Chen C, Xu T, Yan M, Xue B, Wang Y, Liu C, Zhong T, Wang Z, Meng X, et al: Pseudolaric acid B activates autophagy in MCF-7 human breast cancer cells to prevent cell death. Oncol Lett. 11:1731–1737. 2016. View Article : Google Scholar : PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Pseudolaric acid B induces apoptosis associated with the mitochondrial and PI3K/AKT/mTOR pathways in triple‑negative breast cancer

This article is mentioned in:

Abstract

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Related Articles