Protodioscin Induces Mitochondrial Apoptosis of Human Hepatocellular Carcinoma Cells Through Eliciting ER Stress-Mediated IP3R Targeting Mfn1/Bak Expression

Overview

Journal J Hepatocell Carcinoma

Date 2022 May 2

PMID 35496076

Authors

Chen-Lin Yu

Hsiang-Lin Lee

Shun-Fa Yang

Shih-Wei Wang

Ching-Pin Lin

Yi-Hsien Hsieh

Hui-Ling Chiou

Affiliations

Soon will be listed here.

Abstract

Objective: Protodioscin (PD), a steroidal saponin, has a diverse pharmacological activity including neuroprotection, male fertility improvement, and cytotoxicity against various cancers cell lines of different origins. However, the effect of PD on hepatocellular carcinoma (HCC) is still unclear.

Methods: Cell viability, colony formation and flow cytometry analysis for apoptosis profile, mitochondrial membrane potential endoplasmic reticulum (ER) expansion were employed to determine the effect of PD against HCC cells. Transient transfection of siRNA, immunofluorescent imaging and immunoprecipitation were used to elucidate the anti-cancer mechanism of PD. The in vivo toxicity and efficacy of PD were assessed by a xenograft mouse model.

Results: PD induced apoptosis, loss of mitochondrial membrane potential and ER expansion in HCC cells. Either downregulation of Mfn1 or Bak reversed PD-induced apoptosis and loss of mitochondrial membrane potential. Further analysis revealed that Mfn1 and Bak will form a complex with IP3R to facilitate the transfer of Ca from ER to mitochondria and apoptosis. In addition, our tumour xenograft model further verifies the in vivo anti-tumour effect of PD.

Conclusion: Our study sheds light on the understanding of the anti-HCC effects of PD and may open new aspects for the development of novel treatment for human hepatocellular carcinoma.

Citing Articles

Assessments of protodioscin's antinociceptive and antidiarrheal properties: in vivo and in silico investigations on macromolecule binding affinity and modulatory effects.

Ghosh P, Al Hasan M, Rouf R, Chowdhury R, Yadav B, Mia E Naunyn Schmiedebergs Arch Pharmacol. 2025; .

PMID: 39921733 DOI: 10.1007/s00210-025-03860-2.

A detailed review of pharmacology of MFN1 (mitofusion-1)-mediated mitochondrial dynamics: Implications for cellular health and diseases.

Alghamdi A Saudi Pharm J. 2024; 32(4):102012.

PMID: 38463181 PMC: 10924208. DOI: 10.1016/j.jsps.2024.102012.

The role of mitochondrial dynamics in disease.

Wang Y, Dai X, Li H, Jiang H, Zhou J, Zhang S MedComm (2020). 2023; 4(6):e462.

PMID: 38156294 PMC: 10753647. DOI: 10.1002/mco2.462.

Recent advances in melittin-based nanoparticles for antitumor treatment: from mechanisms to targeted delivery strategies.

Yu X, Jia S, Yu S, Chen Y, Zhang C, Chen H J Nanobiotechnology. 2023; 21(1):454.

PMID: 38017537 PMC: 10685715. DOI: 10.1186/s12951-023-02223-4.

Mitochondrial Dynamics in Neurodegenerative Diseases: Unraveling the Role of Fusion and Fission Processes.

Grel H, Woznica D, Ratajczak K, Kalwarczyk E, Anchimowicz J, Switlik W Int J Mol Sci. 2023; 24(17).

PMID: 37685840 PMC: 10487704. DOI: 10.3390/ijms241713033.

References

Oyama M, Tokiwano T, Kawaii S, Yoshida Y, Mizuno K, Oh K . Protodioscin, Isolated from the Rhizome of Collected in Northern Japan is the Major Antiproliferative Compound to HL-60  Leukemic Cells. Curr Bioact Compd. 2017; 13(2):170-174. PMC: 5396219. DOI: 10.2174/1573407213666170113123428. View

Li J, Li Y, Jiao J, Wang J, Li Y, Qin D . Mitofusin 1 is negatively regulated by microRNA 140 in cardiomyocyte apoptosis. Mol Cell Biol. 2014; 34(10):1788-99. PMC: 4019028. DOI: 10.1128/MCB.00774-13. View

Lin J, Li H, Yasumura D, Cohen H, Zhang C, Panning B . IRE1 signaling affects cell fate during the unfolded protein response. Science. 2007; 318(5852):944-9. PMC: 3670588. DOI: 10.1126/science.1146361. View

Yang S, Zhou R, Zhang C, He S, Su Z . Mitochondria-Associated Endoplasmic Reticulum Membranes in the Pathogenesis of Type 2 Diabetes Mellitus. Front Cell Dev Biol. 2020; 8:571554. PMC: 7606698. DOI: 10.3389/fcell.2020.571554. View

Westermann B . Bioenergetic role of mitochondrial fusion and fission. Biochim Biophys Acta. 2012; 1817(10):1833-8. DOI: 10.1016/j.bbabio.2012.02.033. View

Hibasami H, Moteki H, Ishikawa K, Katsuzaki H, Imai K, Yoshioka K . Protodioscin isolated from fenugreek (Trigonella foenumgraecum L.) induces cell death and morphological change indicative of apoptosis in leukemic cell line H-60, but not in gastric cancer cell line KATO III. Int J Mol Med. 2002; 11(1):23-6. View

Lin C, Lee C, Chen C, Cheng C, Chen P, Ying T . Protodioscin Induces Apoptosis Through ROS-Mediated Endoplasmic Reticulum Stress via the JNK/p38 Activation Pathways in Human Cervical Cancer Cells. Cell Physiol Biochem. 2018; 46(1):322-334. DOI: 10.1159/000488433. View

Akinyemiju T, Abera S, Ahmed M, Alam N, Alemayohu M, Allen C . The Burden of Primary Liver Cancer and Underlying Etiologies From 1990 to 2015 at the Global, Regional, and National Level: Results From the Global Burden of Disease Study 2015. JAMA Oncol. 2017; 3(12):1683-1691. PMC: 5824275. DOI: 10.1001/jamaoncol.2017.3055. View

Almanza A, Carlesso A, Chintha C, Creedican S, Doultsinos D, Leuzzi B . Endoplasmic reticulum stress signalling - from basic mechanisms to clinical applications. FEBS J. 2018; 286(2):241-278. PMC: 7379631. DOI: 10.1111/febs.14608. View

10.

Kroemer G, Galluzzi L, Brenner C . Mitochondrial membrane permeabilization in cell death. Physiol Rev. 2007; 87(1):99-163. DOI: 10.1152/physrev.00013.2006. View

11.

Pyakurel A, Savoia C, Hess D, Scorrano L . Extracellular regulated kinase phosphorylates mitofusin 1 to control mitochondrial morphology and apoptosis. Mol Cell. 2015; 58(2):244-54. PMC: 4405354. DOI: 10.1016/j.molcel.2015.02.021. View

12.

Vervliet T, Parys J, Bultynck G . Bcl-2 proteins and calcium signaling: complexity beneath the surface. Oncogene. 2016; 35(39):5079-92. DOI: 10.1038/onc.2016.31. View

13.

Man S, Luo C, Yan M, Zhao G, Ma L, Gao W . Treatment for liver cancer: From sorafenib to natural products. Eur J Med Chem. 2021; 224:113690. DOI: 10.1016/j.ejmech.2021.113690. View

14.

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View

15.

Yeh T, Chiang P, Li T, Hsu J, Lin C, Wang S . Genistein induces apoptosis in human hepatocellular carcinomas via interaction of endoplasmic reticulum stress and mitochondrial insult. Biochem Pharmacol. 2006; 73(6):782-92. DOI: 10.1016/j.bcp.2006.11.027. View

16.

Yang H, Niemeijer M, van de Water B, Beltman J . ATF6 Is a Critical Determinant of CHOP Dynamics during the Unfolded Protein Response. iScience. 2020; 23(2):100860. PMC: 7005498. DOI: 10.1016/j.isci.2020.100860. View

17.

Martucciello S, Masullo M, Cerulli A, Piacente S . Natural Products Targeting ER Stress, and the Functional Link to Mitochondria. Int J Mol Sci. 2020; 21(6). PMC: 7139827. DOI: 10.3390/ijms21061905. View

18.

Lin Y, Jiang M, Chen W, Zhao T, Wei Y . Cancer and ER stress: Mutual crosstalk between autophagy, oxidative stress and inflammatory response. Biomed Pharmacother. 2019; 118:109249. DOI: 10.1016/j.biopha.2019.109249. View

19.

Zemirli N, Morel E, Molino D . Mitochondrial Dynamics in Basal and Stressful Conditions. Int J Mol Sci. 2018; 19(2). PMC: 5855786. DOI: 10.3390/ijms19020564. View

20.

Brooks C, Wei Q, Feng L, Dong G, Tao Y, Mei L . Bak regulates mitochondrial morphology and pathology during apoptosis by interacting with mitofusins. Proc Natl Acad Sci U S A. 2007; 104(28):11649-54. PMC: 1913853. DOI: 10.1073/pnas.0703976104. View