{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T13:01:12Z","timestamp":1789563672159,"version":"build-2803163510"},"reference-count":37,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,8,27]],"date-time":"2022-08-27T00:00:00Z","timestamp":1661558400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Chinese National Natural Science Foundation","award":["31861143050"],"award-info":[{"award-number":["31861143050"]}]},{"name":"Chinese National Natural Science Foundation","award":["31772476"],"award-info":[{"award-number":["31772476"]}]},{"name":"Chinese National Natural Science Foundation","award":["31911530077"],"award-info":[{"award-number":["31911530077"]}]},{"name":"Chinese National Natural Science Foundation","award":["82070038"],"award-info":[{"award-number":["82070038"]}]},{"name":"Academy of Scientific Research and Technology (ASRT, Egypt; China-Egypt Scientific and Technological Cooperation Program)","award":["31861143050"],"award-info":[{"award-number":["31861143050"]}]},{"name":"Academy of Scientific Research and Technology (ASRT, Egypt; China-Egypt Scientific and Technological Cooperation Program)","award":["31772476"],"award-info":[{"award-number":["31772476"]}]},{"name":"Academy of Scientific Research and Technology (ASRT, Egypt; China-Egypt Scientific and Technological Cooperation Program)","award":["31911530077"],"award-info":[{"award-number":["31911530077"]}]},{"name":"Academy of Scientific Research and Technology (ASRT, Egypt; China-Egypt Scientific and Technological Cooperation Program)","award":["82070038"],"award-info":[{"award-number":["82070038"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Non-small cell lung cancer (NSCLC) is the leading cause of death in lung cancer due to its aggressiveness and rapid migration. The potent antitumor effect of Smp24, an antimicrobial peptide derived from Egyptian scorpion Scorpio maurus palmatus via damaging the membrane and cytoskeleton have been reported earlier. However, its effects on mitochondrial functions and ROS accumulation in human lung cancer cells remain unknown. In the current study, we discovered that Smp24 can interact with the cell membrane and be internalized into A549 cells via endocytosis, followed by targeting mitochondria and affect mitochondrial function, which significantly causes ROS overproduction, altering mitochondrial membrane potential and the expression of cell cycle distribution-related proteins, mitochondrial apoptotic pathway, MAPK, as well as PI3K\/Akt\/mTOR\/FAK signaling pathways. In summary, the antitumor effect of Smp24 against A549 cells is related to the induction of apoptosis, autophagy plus cell cycle arrest via mitochondrial dysfunction, and ROS accumulation. Accordingly, our findings shed light on the anticancer mechanism of Smp24, which may contribute to its further development as a potential agent in the treatment of lung cancer cells.<\/jats:p>","DOI":"10.3390\/toxins14090590","type":"journal-article","created":{"date-parts":[[2022,8,31]],"date-time":"2022-08-31T02:09:36Z","timestamp":1661911776000},"page":"590","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["The Strong Anti-Tumor Effect of Smp24 in Lung Adenocarcinoma A549 Cells Depends on Its Induction of Mitochondrial Dysfunctions and ROS Accumulation"],"prefix":"10.3390","volume":"14","author":[{"given":"Ruiyin","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China"},{"name":"Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuewen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tienthanh","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China"},{"name":"Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinwei","family":"Chai","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yahua","family":"Gao","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiena","family":"Wu","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinqiao","family":"Li","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3862-5535","authenticated-orcid":false,"given":"Mohamed A.","family":"Abdel-Rahman","sequence":"additional","affiliation":[{"name":"Zoology Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4525-5803","authenticated-orcid":false,"given":"Xueqing","family":"Xu","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1038\/nature25183","article-title":"The biology and management of non-small cell lung cancer","volume":"553","author":"Herbst","year":"2018","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Tornesello, A.L., Borrelli, A., Buonaguro, L., Buonaguro, F.M., and Tornesello, M.L. (2020). Antimicrobial Peptides as Anticancer Agents: Functional Properties and Biological Activities. Molecules, 25.","DOI":"10.3390\/molecules25122850"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.1021\/cr4006704","article-title":"The chemistry and biological activities of peptides from amphibian skin secretions","volume":"115","author":"Xu","year":"2015","journal-title":"Chem. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.4014\/jmb.1205.05041","article-title":"The novel biological action of antimicrobial peptides via apoptosis induction","volume":"22","author":"Cho","year":"2012","journal-title":"J. Microbiol. Biotechnol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3186","DOI":"10.3748\/wjg.v22.i11.3186","article-title":"Melittin induces human gastric cancer cell apoptosis via activation of mitochondrial pathway","volume":"22","author":"Kong","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Ju, X., Fan, D., Kong, L., Yang, Q., Zhu, Y., Zhang, S., Su, G., and Li, Y. (2021). Antimicrobial Peptide Brevinin-1RL1 from Frog Skin Secretion Induces Apoptosis and Necrosis of Tumor Cells. Molecules, 26.","DOI":"10.3390\/molecules26072059"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Kuo, H.M., Tseng, C.C., Chen, N.F., Tai, M.H., Hung, H.C., Feng, C.W., Cheng, S.Y., Huang, S.Y., Jean, Y.H., and Wen, Z.H. (2018). MSP-4, an Antimicrobial Peptide, Induces Apoptosis via Activation of Extrinsic Fas\/FasL- and Intrinsic Mitochondria-Mediated Pathways in One Osteosarcoma Cell Line. Mar. Drugs, 16.","DOI":"10.3390\/md16010008"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Chen, Y.P., Shih, P.C., Feng, C.W., Wu, C.C., Tsui, K.H., Lin, Y.H., Kuo, H.M., and Wen, Z.H. (2021). Pardaxin Activates Excessive Mitophagy and Mitochondria-Mediated Apoptosis in Human Ovarian Cancer by Inducing Reactive Oxygen Species. Antioxidants, 10.","DOI":"10.3390\/antiox10121883"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3147","DOI":"10.1021\/acs.jnatprod.1c00963","article-title":"Antitumor Effects of Scorpion Peptide Smp43 through Mitochondrial Dysfunction and Membrane Disruption on Hepatocellular Carcinoma","volume":"84","author":"Chai","year":"2021","journal-title":"J. Nat. Prod."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Guo, R., Liu, J., Chai, J., Gao, Y., Abdel-Rahman, M.A., and Xu, X. (2022). Scorpion Peptide Smp24 Exhibits a Potent Antitumor Effect on Human Lung Cancer Cells by Damaging the Membrane and Cytoskeleton In Vivo and In Vitro. Toxins, 14.","DOI":"10.3390\/toxins14070438"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"788874","DOI":"10.3389\/fphar.2021.788874","article-title":"Scorpion Venom Antimicrobial Peptides Induce Caspase-1 Dependant Pyroptotic Cell Death","volume":"12","author":"Elrayess","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2737","DOI":"10.1016\/j.bbamem.2016.07.018","article-title":"Phospholipid dependent mechanism of smp24, an \u03b1-helical antimicrobial peptide from scorpion venom","volume":"1858","author":"Harrison","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1007\/s00249-010-0661-4","article-title":"Using zeta-potential measurements to quantify peptide partition to lipid membranes","volume":"40","author":"Freire","year":"2011","journal-title":"Eur. Biophys. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4673","DOI":"10.1039\/c4ob00673a","article-title":"Interaction of amphiphilic \u03b1-helical cell-penetrating peptides with heparan sulfate","volume":"12","author":"Yang","year":"2014","journal-title":"Org. Biomol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"31192","DOI":"10.1074\/jbc.M303938200","article-title":"Studies on the internalization mechanism of cationic cell-penetrating peptides","volume":"278","author":"Drin","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2570","DOI":"10.1002\/jcp.25349","article-title":"Mitochondria and Mitochondrial ROS in Cancer: Novel Targets for Anticancer Therapy","volume":"231","author":"Yang","year":"2016","journal-title":"J. Cell Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/nri3495","article-title":"Mitogen-activated protein kinases in innate immunity","volume":"13","author":"Arthur","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s10059-010-0028-9","article-title":"Melittin suppresses PMA-induced tumor cell invasion by inhibiting NF-kappaB and AP-1-dependent MMP-9 expression","volume":"29","author":"Park","year":"2010","journal-title":"Mol. Cells"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Lim, H.N., Baek, S.B., and Jung, H.J. (2019). Bee Venom and Its Peptide Component Melittin Suppress Growth and Migration of Melanoma Cells via Inhibition of PI3K\/AKT\/mTOR and MAPK Pathways. Molecules, 24.","DOI":"10.3390\/molecules24050929"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Hmed, B., Serria, H.T., and Mounir, Z.K. (2013). Scorpion peptides: Potential use for new drug development. J. Toxicol., 958797.","DOI":"10.1155\/2013\/958797"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.ejphar.2009.08.043","article-title":"Cationic amphiphilic peptides with cancer-selective toxicity","volume":"625","author":"Schweizer","year":"2009","journal-title":"Eur. J. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1016\/S0006-3495(01)75802-X","article-title":"Barrel-stave model or toroidal model? A case study on melittin pores","volume":"81","author":"Yang","year":"2001","journal-title":"Biophys. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"690","DOI":"10.3389\/fendo.2019.00690","article-title":"Mitochondrial Dysfunction Pathway Networks and Mitochondrial Dynamics in the Pathogenesis of Pituitary Adenomas","volume":"10","author":"Li","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/s10863-016-9669-5","article-title":"p53 and mitochondrial dysfunction: Novel insight of neurodegenerative diseases","volume":"48","author":"Dai","year":"2016","journal-title":"J. Bioenerg. Biomembr."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1111\/jcmm.12001","article-title":"Interconnections between apoptotic, autophagic and necrotic pathways: Implications for cancer therapy development","volume":"17","author":"Jain","year":"2013","journal-title":"J. Cell. Mol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"102748","DOI":"10.1016\/j.dnarep.2019.102748","article-title":"Entrenching role of cell cycle checkpoints and autophagy for maintenance of genomic integrity","volume":"86","author":"Anand","year":"2020","journal-title":"DNA Repair"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1097\/CCO.0b013e32835b639e","article-title":"p21WAF1 and tumourigenesis: 20 years after","volume":"25","author":"Warfel","year":"2013","journal-title":"Curr. Opin. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Wu, G., Lin, N., Xu, L., Liu, B., and Feitelson, M.A. (2013). Feitelson, UCN-01 induces S and G2\/M cell cycle arrest through the p53\/p21(waf1) or CHK2\/CDC25C pathways and can suppress invasion in human hepatoma cell lines. BMC Cancer, 13.","DOI":"10.1186\/1471-2407-13-167"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.semcdb.2005.02.007","article-title":"New insights into cyclins, CDKs, and cell cycle control","volume":"16","author":"Dynlacht","year":"2005","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1038\/cdd.2009.28","article-title":"PUMA- and Bax-induced autophagy contributes to apoptosis","volume":"16","author":"Yee","year":"2009","journal-title":"Cell Death Differ."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Ren, S.X., Shen, J., Cheng, A.S., Lu, L., Chan, R.L., Li, Z.J., Wang, X.J., Wong, C.C., Zhang, L., and Ng, S.S. (2013). FK-16 derived from the anticancer peptide LL-37 induces caspase-independent apoptosis and autophagic cell death in colon cancer cells. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0063641"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Ma, S., Huang, D., Zhai, M., Yang, L., Peng, S., Chen, C., Feng, X., Weng, Q., Zhang, B., and Xu, M. (2015). Isolation of a novel bio-peptide from walnut residual protein inducing apoptosis and autophagy on cancer cells. BMC Complement. Altern. Med., 15.","DOI":"10.1186\/s12906-015-0940-9"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1111\/j.1582-4934.2008.00129.x","article-title":"Brevinin-2R(1) semi-selectively kills cancer cells by a distinct mechanism, which involves the lysosomal-mitochondrial death pathway","volume":"12","author":"Ghavami","year":"2008","journal-title":"J. Cell Mol. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"710","DOI":"10.3892\/etm.2021.10142","article-title":"Autophagy-related signaling pathways are involved in cancer (Review)","volume":"22","author":"Chen","year":"2021","journal-title":"Exp. Ther. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1517\/14728222.2011.645805","article-title":"Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy","volume":"16","author":"Santarpia","year":"2012","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Guo, M., Liu, Z., Si, J., Zhang, J., Zhao, J., Guo, Z., Xie, Y., Zhang, H., and Gan, L. (2021). Cediranib Induces Apoptosis, G1 Phase Cell Cycle Arrest, and Autophagy in Non-Small-Cell Lung Cancer Cell A549 In Vitro. Biomed. Res. Int., 5582648.","DOI":"10.1155\/2021\/5582648"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"783108","DOI":"10.3389\/fphar.2021.783108","article-title":"Antimicrobial and Anti-inflammatory Effects of a Novel Peptide From the Skin of Frog Microhyla pulchra","volume":"12","author":"Tian","year":"2021","journal-title":"Front. Pharmacol."}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/14\/9\/590\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:16:24Z","timestamp":1760141784000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/14\/9\/590"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,27]]},"references-count":37,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["toxins14090590"],"URL":"https:\/\/doi.org\/10.3390\/toxins14090590","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,27]]}}}