Kaempferide triggers apoptosis and paraptosis in pancreatic tumor cells by modulating the ROS production, SHP-1 expression, and the STAT3 pathway.
| Title: | Kaempferide triggers apoptosis and paraptosis in pancreatic tumor cells by modulating the ROS production, SHP-1 expression, and the STAT3 pathway. |
|---|---|
| Authors: | Jung YY; Department of Science in Korean Medicine, Kyung Hee University, Dongdaemun-gu, Seoul, Republic of Korea.; Son NT; Institute of Chemistry, Vietnam Academy of Science and Technology (VAST), Hoang Quoc Viet, Caugiay, Hanoi, Vietnam.; Department of Chemistry, Graduate University of Science and Technology, VAST, Hoang Quoc Viet, Caugiay, Hanoi, Vietnam.; University of São Paulo (USP), School of Pharmaceutical Sciences of Ribeirão Preto, SP, Brazil.; Mohan CD; FEST Division, CSIR-Indian Institute of Toxicology Research, Lucknow, Uttar Pradesh, India.; Bastos JK; University of São Paulo (USP), School of Pharmaceutical Sciences of Ribeirão Preto, SP, Brazil.; Luyen ND; Institute of Natural Products Chemistry, VAST, Hoang Quoc Viet, Caugiay, Hanoi, Vietnam.; Huong LM; Institute of Natural Products Chemistry, VAST, Hoang Quoc Viet, Caugiay, Hanoi, Vietnam.; Ahn KS; Department of Science in Korean Medicine, Kyung Hee University, Dongdaemun-gu, Seoul, Republic of Korea. |
| Source: | IUBMB life [IUBMB Life] 2024 Sep; Vol. 76 (9), pp. 745-759. Date of Electronic Publication: 2024 May 06. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Published for the International Union of Biochemistry and Molecular Biology by Taylor & Francis Country of Publication: England NLM ID: 100888706 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-6551 (Electronic) Linking ISSN: 15216543 NLM ISO Abbreviation: IUBMB Life Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: London ; Philadelphia, PA : Published for the International Union of Biochemistry and Molecular Biology by Taylor & Francis, c1999- |
| MeSH Terms: | STAT3 Transcription Factor*/metabolism ; STAT3 Transcription Factor*/genetics ; Pancreatic Neoplasms*/pathology ; Pancreatic Neoplasms*/metabolism ; Pancreatic Neoplasms*/drug therapy ; Pancreatic Neoplasms*/genetics ; Apoptosis*/drug effects ; Reactive Oxygen Species*/metabolism ; Protein Tyrosine Phosphatase, Non-Receptor Type 6*/metabolism ; Protein Tyrosine Phosphatase, Non-Receptor Type 6*/genetics ; Signal Transduction*/drug effects; Kaempferols/pharmacology ; Gene Expression Regulation, Neoplastic/drug effects ; Cell Proliferation/drug effects ; Humans ; Cell Line, Tumor ; Paraptosis |
| Abstract: | Pancreatic cancer is one of the deadliest diseases with a poor prognosis and a five-survival rate. The STAT3 pathway is hyperactivated which contributes to the sustained proliferative signals in pancreatic cancer cells. We have isolated kaempferide (KF), an O-methylated flavonol, from the green propolis of Mimosa tenuiflora and examined its effect on two forms of cell death namely, apoptosis and paraptosis. KF significantly increased the cleavage of caspase-3 and PARP. It also downmodulated the expression of Alix (an intracellular inhibitor of paraptosis) and increased the expression of CHOP and ATF4 (transcription factors that promote paraptosis) indicating that KF promotes apoptosis as well as paraptosis. KF also increased intracellular reactive oxygen species (ROS) suggesting the perturbance of the redox state. N-acetylcysteine reverted the apoptosis- and paraptosis-inducing effects of KF. Some ROS inducers are known to suppress the STAT3 pathway and investigation revealed that KF downmodulates STAT3 and its upstream kinases (JAK1, JAK2, and Src). Additionally, KF also elevated the expression of SHP-1, a tyrosine phosphatase which is involved in the negative modulation of the STAT3 pathway. Knockdown of SHP-1 prevented KF-driven STAT3 inhibition. Altogether, KF has been identified as a promoter of apoptosis and paraptosis in pancreatic cancer cells through the elevation of ROS generation and SHP-1 expression.; (© 2024 International Union of Biochemistry and Molecular Biology.) |
| References: | Ashrafizadeh M, Mohan CD, Rangappa S, Zarrabi A, Hushmandi K, Kumar AP, et al. Noncoding RNAs as regulators of STAT3 pathway in gastrointestinal cancers: roles in cancer progression and therapeutic response. Med Res Rev. 2023;43:1263–1321.; Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74:2913–2921.; Ramai D, Facciorusso A, Hart PA, Barakat MT. Rising incidence of pancreatic cancer in patients 20 to 39 years: a population‐based observational study. Pancreas. 2023;52:e213–e215.; Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72:7–33.; Ramai D, Lanke G, Lai J, Barakat M, Chandan S, Ofosu A, et al. Early‐ and late‐onset pancreatic adenocarcinoma: a population‐based comparative study. Pancreatology. 2021;21:124–129.; Leinwand J, Miller G. Regulation and modulation of antitumor immunity in pancreatic cancer. Nat Immunol. 2020;21:1152–1159.; Chopra P, Sethi G, Dastidar SG, Ray A. Polo‐like kinase inhibitors: an emerging opportunity for cancer therapeutics. Expert Opin Investig Drugs. 2010;19:27–43.; Dey A, Wong E, Kua N, Teo HL, Tergaonkar V, Lane D. Hexamethylene bisacetamide (HMBA) simultaneously targets AKT and MAPK pathway and represses NF kappaB activity: implications for cancer therapy. Cell Cycle. 2008;7:3759–3767.; Dey A, Wong ET, Bist P, Tergaonkar V, Lane DP. Nutlin‐3 inhibits the NFkappaB pathway in a p53‐dependent manner: implications in lung cancer therapy. Cell Cycle. 2007;6:2178–2185.; Mohan CD, Rangappa S, Nayak SC, Jadimurthy R, Wang L, Sethi G, et al. Bacteria as a treasure house of secondary metabolites with anticancer potential. Semin Cancer Biol. 2022;86:998–1013.; Wu Q, Wu W, Fu B, Shi L, Wang X, Kuca K. JNK signaling in cancer cell survival. Med Res Rev. 2019;39:2082–2104.; Yang MH, Ha IJ, Lee S‐G, Lee J, Um J‐Y, Sethi G, et al. Brassinin induces apoptosis, autophagy, and Paraptosis via MAPK signaling pathway activation in chronic myelogenous leukemia cells. Biology. 2023;12:307.; Yumnam S, Park HS, Kim MK, Nagappan A, Hong GE, Lee HJ, et al. Hesperidin induces paraptosis like cell death in hepatoblatoma, HepG2 cells: involvement of ERK1/2 MAPK. PLoS One. 2014;9:e101321.; Mohan CD, Rangappa S, Nayak SC, Sethi G, Rangappa KS. Paradoxical functions of long noncoding RNAs in modulating STAT3 signaling pathway in hepatocellular carcinoma. Biochim Biophys Acta – Rev Cancer. 2021;1876:188574.; Mohan CD, Rangappa S, Preetham HD, Chandra NS, Gupta VK, Basappa S, et al. Targeting STAT3 signaling pathway in cancer by agents derived from mother nature. Semin Cancer Biol. 2022;80:157–182.; Tan SM, Li F, Rajendran P, Kumar AP, Hui KM, Sethi G. Identification of beta‐escin as a novel inhibitor of signal transducer and activator of transcription 3/Janus‐activated kinase 2 signaling pathway that suppresses proliferation and induces apoptosis in human hepatocellular carcinoma cells. J Pharmacol Exp Ther. 2010;334:285–293.; Baek SH, Lee JH, Kim C, Ko JH, Ryu SH, Lee SG, et al. Ginkgolic acid C 17:1, derived from Ginkgo biloba leaves, suppresses constitutive and inducible STAT3 activation through induction of PTEN and SHP‐1 tyrosine phosphatase. Molecules. 2017;22:276.; Lee JH, Kim C, Ko JH, Jung YY, Jung SH, Kim E, et al. Casticin inhibits growth and enhances ionizing radiation‐induced apoptosis through the suppression of STAT3 signaling cascade. J Cell Biochem. 2019;120:9787–9798.; Zhang L, Kuca K, You L, Zhao Y, Musilek K, Nepovimova E, et al. Signal transducer and activator of transcription 3 signaling in tumor immune evasion. Pharmacol Ther. 2022;230:107969.; Baek SH, Ko JH, Lee H, Jung J, Kong M, Lee JW, et al. Resveratrol inhibits STAT3 signaling pathway through the induction of SOCS‐1: role in apoptosis induction and radiosensitization in head and neck tumor cells. Phytomedicine. 2016;23:566–577.; Hwang ST, Kim C, Lee JH, Chinnathambi A, Alharbi SA, Shair OHM, et al. Cycloastragenol can negate constitutive STAT3 activation and promote paclitaxel‐induced apoptosis in human gastric cancer cells. Phytomedicine. 2019;59:152907.; Jung YY, Lee JH, Nam D, Narula AS, Namjoshi OA, Blough BE, et al. Anti‐myeloma effects of icariin are mediated through the attenuation of JAK/STAT3‐dependent signaling Cascade. Front Pharmacol. 2018;9:531.; Yang MH, Jung SH, Chinnathambi A, Alahmadi TA, Alharbi SA, Sethi G, et al. Attenuation of STAT3 signaling cascade by daidzin can enhance the apoptotic potential of bortezomib against multiple myeloma. Biomolecules. 2020;10:23.; Jung YY, Ko J‐H, Um J‐Y, Chinnathambi A, Alharbi SA, Sethi G, et al. LDL cholesterol promotes the proliferation of prostate and pancreatic cancer cells by activating the STAT3 pathway. J Cell Physiol. 2021;236:5253–5264.; Jung YY, Shanmugam MK, Narula AS, Kim C, Lee JH, Namjoshi OA, et al. Oxymatrine attenuates tumor growth and deactivates STAT5 signaling in a lung cancer xenograft model. Cancers. 2019;11:49.; Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell. 2004;116:205–219.; Hassan M, Watari H, AbuAlmaaty A, Ohba Y, Sakuragi N. Apoptosis and molecular targeting therapy in cancer. Biomed Res Int. 2014;2014:150845.; Lopez J, Tait SW. Mitochondrial apoptosis: killing cancer using the enemy within. Br J Cancer. 2015;112:957–962.; Zaman S, Wang R, Gandhi V. Targeting the apoptosis pathway in hematologic malignancies. Leuk Lymphoma. 2014;55:1980–1992.; Ahn KS, Sethi G, Jain AK, Jaiswal AK, Aggarwal BB. Genetic deletion of NAD(P)H:quinone oxidoreductase 1 abrogates activation of nuclear factor‐kappaB, IkappaBalpha kinase, c‐Jun N‐terminal kinase, Akt, p38, and p44/42 mitogen‐activated protein kinases and potentiates apoptosis. J Biol Chem. 2006;281:19798–19808.; Kaufmann SH, Desnoyers S, Ottaviano Y, Davidson NE, Poirier GG. Specific proteolytic cleavage of poly(ADP‐ribose) polymerase: an early marker of chemotherapy‐induced apoptosis. Cancer Res. 1993;53:3976–3985.; Lazebnik YA, Kaufmann SH, Desnoyers S, Poirier GG, Earnshaw WC. Cleavage of poly(ADP‐ribose) polymerase by a proteinase with properties like ICE. Nature. 1994;371:346–347.; Los M, Herr I, Friesen C, Fulda S, Schulze‐Osthoff K, Debatin KM. Cross‐resistance of CD95‐ and drug‐induced apoptosis as a consequence of deficient activation of caspases (ICE/Ced‐3 proteases). Blood. 1997;90:3118–3129.; Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, et al. Identification and inhibition of the ICE/CED‐3 protease necessary for mammalian apoptosis. Nature. 1995;376:37–43.; Sethi G, Ahn KS, Sandur SK, Lin X, Chaturvedi MM, Aggarwal BB. Indirubin enhances tumor necrosis factor‐induced apoptosis through modulation of nuclear factor‐kappa B signaling pathway. J Biol Chem. 2006;281:23425–23435.; Sethi G, Sung B, Kunnumakkara AB, Aggarwal BB. Targeting TNF for treatment of cancer and autoimmunity. Adv Exp Med Biol. 2009;647:37–51.; Fontana F, Raimondi M, Marzagalli M, Di Domizio A, Limonta P. The emerging role of paraptosis in tumor cell biology: perspectives for cancer prevention and therapy with natural compounds. Biochim Biophys Acta Rev Cancer. 2020;1873:188338.; Lee D, Kim IY, Saha S, Choi KS. Paraptosis in the anti‐cancer arsenal of natural products. Pharmacol Ther. 2016;162:120–133.; Sperandio S, de Belle I, Bredesen DE. An alternative, nonapoptotic form of programmed cell death. Proc Natl Acad Sci U S A. 2000;97:14376–14381.; Wang Y, Wen X, Zhang N, Wang L, Hao D, Jiang X, et al. Small‐molecule compounds target paraptosis to improve cancer therapy. Biomed Pharmacother. 2019;118:109203.; Sperandio S, Poksay K, de Belle I, Lafuente MJ, Liu B, Nasir J, et al. Paraptosis: mediation by MAP kinases and inhibition by AIP‐1/Alix. Cell Death Differ. 2004;11:1066–1075.; Uzma F, Mohan CD, Hashem A, Konappa NM, Rangappa S, Kamath PV, et al. Endophytic fungi—alternative sources of cytotoxic compounds: a review. Front Pharmacol. 2018;9:309.; Li HL, Li SM, Luo YH, Xu WT, Zhang Y, Zhang T, et al. Kaempferide induces G0/G1 phase arrest and apoptosis via ROS‐mediated signaling pathways in A549 human lung cancer cells. Nat Prod Commun. 2020;15:1934578X2093522.; Jung YY, Ha IJ, Um JY, Sethi G, Ahn KS. Fangchinoline diminishes STAT3 activation by stimulating oxidative stress and targeting SHP‐1 protein in multiple myeloma model. J Adv Res. 2022;35:245–257.; Alicea‐Velazquez NL, Jakoncic J, Boggon TJ. Structure‐guided studies of the SHP‐1/JAK1 interaction provide new insights into phosphatase catalytic domain substrate recognition. J Struct Biol. 2013;181:243–251.; Paling NR, Welham MJ. Role of the protein tyrosine phosphatase SHP‐1 (Src homology phosphatase‐1) in the regulation of interleukin‐3‐induced survival, proliferation and signalling. Biochem J. 2002;368:885–894.; Tsui HW, Hasselblatt K, Martin A, Mok SC, Tsui FW. Molecular mechanisms underlying SHP‐1 gene expression. Eur J Biochem. 2002;269:3057–3064.; Hu MH, Chen LJ, Chen YL, Tsai MS, Shiau CW, Chao TI, et al. Targeting SHP‐1‐STAT3 signaling: a promising therapeutic approach for the treatment of cholangiocarcinoma. Oncotarget. 2017;8:65077–65089.; Huang TT, Su JC, Liu CY, Shiau CW, Chen KF. Alteration of SHP‐1/p‐STAT3 signaling: a potential target for anticancer therapy. Int J Mol Sci. 2017;18:1234.; Mello BCBS, Petrus JCC, Hubinger MD. Concentration of flavonoids and phenolic compounds in aqueous and ethanolic propolis extracts through nanofiltration. J Food Eng. 2010;96:533–539.; Nath LR, Gorantla JN, Joseph SM, Antony J, Thankachan S, Menon DB, et al. Kaempferide, the most active among the four flavonoids isolated and characterized from Chromolaena odorata, induces apoptosis in cervical cancer cells while being pharmacologically safe. RSC Adv. 2015;5:100912–100922.; Loh YS, Li G, Fan K, Ahmed I, Roufogalis B, Sze D. Kaempferide targets side population, the putative cancer stem cell, in myeloma and induced apoptosis in dose‐dependant manner. Blood. 2010;116:5029.; Martineti V, Tognarini I, Azzari C, Sala SC, Clematis F, Dolci M, et al. Inhibition of in vitro growth and arrest in the G0/G1 phase of HCT8 line human colon cancer cells by kaempferide triglycoside from Dianthus caryophyllus. Phytother Res. 2010;24:1302–1308.; Eguchi H, Matsunaga T, Endo S, Ichihara K, Ikari A. Kaempferide enhances chemosensitivity of human lung adenocarcinoma A549 cells mediated by the decrease in phosphorylation of Akt and Claudin‐2 expression. Nutrients. 2020;12:1190.; Hanson S, Dharan A, Jinsha PV, Pal S, Nair BG, Kar R, et al. Paraptosis: a unique cell death mode for targeting cancer. Front Pharmacol. 2023;14:1159409.; Yoon MJ, Kang YJ, Lee JA, Kim IY, Kim MA, Lee YS, et al. Stronger proteasomal inhibition and higher CHOP induction are responsible for more effective induction of paraptosis by dimethoxycurcumin than curcumin. Cell Death Dis. 2014;5:e1112.; Trioulier Y, Torch S, Blot B, Cristina N, Chatellard‐Causse C, Verna JM, et al. Alix, a protein regulating endosomal trafficking, is involved in neuronal death. J Biol Chem. 2004;279:2046–2052.; Balachandran C, Yokoi K, Naito K, Haribabu J, Tamura Y, Umezawa M, et al. Cyclometalated iridium(III) complex–;cationic peptide hybrids trigger Paraptosis in cancer cells via an intracellular Ca2+ overload from the endoplasmic reticulum and a decrease in mitochondrial membrane potential. Molecules. 2021;26:7028.; Choi J‐K, Kwon O‐Y, Lee S‐H. Kaempferide prevents photoaging of ultraviolet‐B irradiated NIH‐3T3 cells and mouse skin via regulating the reactive oxygen species‐mediated signalings. Antioxidants. 2023;12:11.; Shao Y‐F, Tang B‐B, Ding Y‐H, Fang C‐Y, Hong L, Shao C‐X, et al. Kaempferide ameliorates cisplatin‐induced nephrotoxicity via inhibiting oxidative stress and inducing autophagy. Acta Pharmacol Sin. 2023;44:1442–1454.; Tang H, Zeng Q, Ren N, Wei Y, He Q, Chen M, et al. Kaempferide improves oxidative stress and inflammation by inhibiting the TLR4/IκBα/NF‐κB pathway in obese mice. Iran J Basic Med Sci. 2021;24:493–498.; Tie F, Ding J, Hu N, Dong Q, Chen Z, Wang H. Kaempferol and kaempferide attenuate oleic acid‐induced lipid accumulation and oxidative stress in HepG2 cells. Int J Mol Sci. 2021;22:8847.; Choi YK, Kim J, Lee KM, Choi Y‐J, Ye B‐R, Kim M‐S, et al. Tuberatolide B suppresses cancer progression by promoting ROS‐mediated inhibition of STAT3 signaling. Mar Drugs. 2017;15:55.; Xia Y, Wang G, Jiang M, Liu X, Zhao Y, Song Y, et al. A novel biological activity of the STAT3 inhibitor stattic in inhibiting glutathione reductase and suppressing the tumorigenicity of human cervical cancer cells via a ROS‐dependent pathway. Onco Targets Ther. 2021;14:4047–4060.; Zhang J, Ahn KS, Kim C, Shanmugam MK, Siveen KS, Arfuso F, et al. Nimbolide‐induced oxidative stress abrogates STAT3 signaling cascade and inhibits tumor growth in transgenic adenocarcinoma of mouse prostate model. Antioxid Redox Signal. 2016;24:575–589.; Jung YY, Um JY, Nasif O, Alharbi SA, Sethi G, Ahn KS. Blockage of the JAK/STAT3 signaling pathway in multiple myeloma by leelamine. Phytomedicine. 2021;87:153574.; Arora L, Mohan CD, Yang MH, Rangappa S, Deivasigamani A, Kumar AP, et al. Tris(dibenzylideneacetone)dipalladium(0) (Tris DBA) abrogates tumor progression in hepatocellular carcinoma and multiple myeloma preclinical models by regulating the STAT3 signaling pathway. Cancer. 2021;13:5479.; Mohan CD, Bharathkumar H, Bulusu KC, Pandey V, Rangappa S, Fuchs JE, et al. Development of a novel azaspirane that targets the Janus kinase‐signal transducer and activator of transcription (STAT) pathway in hepatocellular carcinoma in vitro and in vivo. J Biol Chem. 2014;289:34296–34307.; Mohan CD, Kim C, Siveen KS, Manu KA, Rangappa S, Chinnathambi A, et al. Crocetin imparts antiproliferative activity via inhibiting STAT3 signaling in hepatocellular carcinoma. IUBMB Life. 2021;73:1348–1362.; Mohan CD, Yang MH, Rangappa S, Chinnathambi A, Alharbi SA, Alahmadi TA, et al. 3‐Formylchromone counteracts STAT3 signaling pathway by elevating SHP‐2 expression in hepatocellular carcinoma. Biology. 2022;11:29. |
| Grant Information: | NRF-2021R1I1A2060024 National Research Foundation of Korea; NRF-2022R1I1A1A01071593 National Research Foundation of Korea; 2017/04138-8 São Paulo Research Foundation |
| Contributed Indexing: | Keywords: SHP‐1; non‐receptor tyrosine kinases; reactive oxygen species; tyrosine phosphatase |
| Substance Nomenclature: | 0 (STAT3 Transcription Factor); 0 (Reactive Oxygen Species); 0 (STAT3 protein, human); EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 6); EC 3.1.3.48 (PTPN6 protein, human); 0 (Kaempferols) |
| Entry Date(s): | Date Created: 20240506 Date Completed: 20240830 Latest Revision: 20250819 |
| Update Code: | 20260130 |
| DOI: | 10.1002/iub.2827 |
| PMID: | 38708996 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't