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Mychonastes sp. 246 Suppresses Human Pancreatic Cancer Cell Growth via IGFBP3- PI3K-mTOR Signaling

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Previously, we confirmed that Mychonastes sp. 246 methanolic extract (ME) markedly reduced the viability of BxPC-3 human pancreatic cancer cells. However, the underlying mechanism ME remained unclear. Hence, we attempted to elucidate the anticancer effect of ME on BxPC-3 human pancreatic cancer cells. First, we investigated the components of ME and their cytotoxicity in normal cells. Then, we confirmed the G1 phase arrest mediated growth inhibitory effect of ME using a cell counting assay and cell cycle analysis. Moreover, we found that the migration-inhibitory effect of ME using a Transwell migration assay. Through RNA sequencing, Gene Ontology-based network analysis, and western blotting, we explored the intracellular mechanisms of ME in BxPC-3 cells. ME modulated the intracellular energy metabolism-related pathway by altering the mRNA levels of IGFBP3 and PPARGC1A in BxPC-3 cells and reduced PI3K and mTOR phosphorylation by upregulating IGFBP3 and 4E-BP1 expression. Finally, we verified that ME reduced the growth of three-dimensional (3D) pancreatic cancer spheroids. Our study demonstrates that ME suppresses pancreatic cancer proliferation through the IGFBP3-PI3K-mTOR signaling pathway. This is the first study on the anticancer effect of the ME against pancreatic cancer, suggesting therapeutic possibilities and the underlying mechanism of ME action.

Abstract

Previously, we confirmed that Mychonastes sp. 246 methanolic extract (ME) markedly reduced the viability of BxPC-3 human pancreatic cancer cells. However, the underlying mechanism ME remained unclear. Hence, we attempted to elucidate the anticancer effect of ME on BxPC-3 human pancreatic cancer cells. First, we investigated the components of ME and their cytotoxicity in normal cells. Then, we confirmed the G1 phase arrest mediated growth inhibitory effect of ME using a cell counting assay and cell cycle analysis. Moreover, we found that the migration-inhibitory effect of ME using a Transwell migration assay. Through RNA sequencing, Gene Ontology-based network analysis, and western blotting, we explored the intracellular mechanisms of ME in BxPC-3 cells. ME modulated the intracellular energy metabolism-related pathway by altering the mRNA levels of IGFBP3 and PPARGC1A in BxPC-3 cells and reduced PI3K and mTOR phosphorylation by upregulating IGFBP3 and 4E-BP1 expression. Finally, we verified that ME reduced the growth of three-dimensional (3D) pancreatic cancer spheroids. Our study demonstrates that ME suppresses pancreatic cancer proliferation through the IGFBP3-PI3K-mTOR signaling pathway. This is the first study on the anticancer effect of the ME against pancreatic cancer, suggesting therapeutic possibilities and the underlying mechanism of ME action.

참고문헌 (67)

  1. Hu JX, "Pancreatic cancer: a review of epidemiology, trend, and risk factors", World J. Gastroenterol, 27, pp.4298~4321 (2021)
  2. Quante AS, "Projections of cancer incidence and cancer-related deaths in Germany by 2020 and 2030", Cancer Med, 5, pp.2649~2656 (2016)
  3. Principe DR, "The current treatment paradigm for pancreatic ductal adenocarcinoma and barriers to therapeutic efficacy", Front. Oncol, 11, pp.688377~ (2021)
  4. Lee Soon, "Gossypol Induces Apoptosis of Human Pancreatic Cancer Cells via CHOP", Endoplasmic Reticulum Stress Signaling Pathway, 2022, pp.32(5), 645~656[DOI]
  5. Springfeld C, "Chemotherapy for pancreatic cancer", Presse Med, 48, pp.e159~e174 (2019)
  6. Dyshlovoy SA, "Marine compounds and cancer: where do we stand?", Mar. Drugs, 13, pp.5657~5665 (2015)
  7. Atanasov AG, "International natural product sciences, T.; supuran, C.T. natural products in drug discovery: advances and opportunities", Nat. Rev. Drug Discov, 20, pp.200~216 (2021)
  8. Borowitzka MA, "Microalgae as sources of pharmaceuticals and other biologically active compounds", J. Appl. Phycol, 7, pp.3~15 (1995)
  9. Becker EW, "Micro-algae as a source of protein", Biotechnol. Adv, 25, pp.207~210 (2007)
  10. Lauritano C, "Bioactivity screening of microalgae for antioxidant, anti-inflammatory, anticancer, anti-diabetes, and antibacterial activities", Front. Mar. Sci, 3, pp.68~ (2016)
  11. 장현진, "토착 담수미세조류 메탄올 추출물의 항산화 및 항암효과", KSBB Journal, 36(2), pp.154~164 (2021), 한국생물공학회[DOI]
  12. Witsch E, "Roles for growth factors in cancer progression", Physiology (Bethesda), 25, pp.85~101 (2010)
  13. Elghazi L, "Role of nutrients and mTOR signaling in the regulation of pancreatic progenitors development", Mol. Metab, 6, pp.560~573 (2017)
  14. Waters AM, "KRAS: the critical driver and therapeutic target for pancreatic cancer", Cold Spring Harb. Perspect. Med, 8, pp.a031435~ (2018)
  15. Iriana S, "Targeting mTOR in pancreatic ductal adenocarcinoma", Front. Oncol, 6, pp.99~ (2016)
  16. Schneeweis C, "Indirect targeting of MYC sensitizes pancreatic cancer cells to mechanistic target of rapamycin (mTOR) inhibition", Cancer Commun. (Lond), 42, pp.360~364 (2022)
  17. Mortazavi M, "Prospects of targeting PI3K", AKT, Crit. Rev. Oncol. Hematol, pp.2022, 176[DOI]
  18. Porta C, "Targeting PI3K", Akt, Front. Oncol, pp.2014, 4[DOI]
  19. Fingar DC, "mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1", eukaryotic translation initiation factor 4E, 2004, pp.24, 200~216
  20. Roncolato F, "PI3K", AKT, Cochrane Database Syst. Rev, pp.2019, 10[DOI]
  21. Lemmon MA, "Cell signaling by receptor tyrosine kinases", Cell, 141, pp.1117~1134 (2010)
  22. Zhao L, "Class I PI3K in oncogenic cellular transformation", Oncogene, 27, pp.5486~5496 (2008)
  23. Trapnell C, "TopHat: discovering splice junctions with RNA-Seq", Bioinformatics, 25, pp.1105~1111 (2009)
  24. Roberts A, "Improving RNA-Seq expression estimates by correcting for fragment bias", Genome Biol, 12, pp.R22~ (2011)
  25. Kielkopf CL, "Bradford assay for determining protein concentration", Cold Spring Harb. Protoc, 2020, pp.102269~ (2020)
  26. López-García J, "HaCaT keratinocytes response on antimicrobial atelocollagen substrates:extent of cytotoxicity, cell viability and proliferation", J. Funct. Biomater, 5, pp.43~57 (2004)
  27. Ayres Pereira M, "Metastasis in pancreatic ductal adenocarcinoma: current standing and methodologies", Genes (Basel), 11, pp.6~ (2019)
  28. Qin C, "Metabolism of pancreatic cancer: paving the way to better anticancer strategies", Mol. Cancer, 19, pp.50~ (2020)
  29. Zhang L, "Challenges in diagnosis of pancreatic cancer", World J. Gastroenterol, 24, pp.2047~2060 (2018)
  30. Lee J, "Gene expression profiles associated with radio-responsiveness in locally advanced rectal cancer", Biology (Basel), 10, pp.500~ (2021)
  31. Faubert B, "Metabolic reprogramming and cancer progression", Science, 368(6487), pp.eaaw5473~ (2020)
  32. Tarrado-Castellarnau M, "Oncogenic regulation of tumor metabolic reprogramming", Oncotarget, 7, pp.62726~62753 (2016)
  33. Mayers JR, "Nature and nurture: what determines tumor metabolic phenotypes?", Cancer Res, 77, pp.3131~3134 (2017)
  34. Minhas AK, "A review on the assessment of stress conditions for simultaneous production of microalgal lipids and carotenoids", Front. Microbiol, 7, pp.546~ (2016)
  35. Yuan C, "Mychonastes afer HSO-3-1 as a potential new source of biodiesel", Biotechnol. Biofuels, 4, pp.47~ (2011)
  36. 차선희, "해양 미세조류 Nannochloropsis oculata 추출ㆍ분획물의 ACE, α-glucosidase 및 암세포 저해 활성", 한국수산과학회지, 43(5), pp.437~444 (2010), 한국수산과학회
  37. Shahzad N, "Phytosterols as a natural anticancer agent: current status and future perspective", Biomed. Pharmacother, 88, pp.786~794 (2017)
  38. Xu H, "Anti-breast-cancer activity exerted by beta-sitosterol-d-glucoside from sweet potato via upregulation of MicroRNA-10a and via the PI3K-Akt signaling pathway", J. Agric. Food Chem, 66, pp.9704~9718 (2018)
  39. Sarkar S, "A novel compound β-sitosterol-3-O-β-D-glucoside isolated from Azadirachta indica effectively induces apoptosis in leukemic cells by targeting G0", G1 populations, 2020, pp.57, 27~32
  40. Andrea Fratter, "New Chitosan Salt in Gastro-Resistant Oral Formulation Could Interfere with Enteric Bile Salts Emulsification of Diet Fats: Preliminary Laboratory Observations and Physiologic Rationale", Journal of Medicinal Food, 17(6), pp.723~729 (2014), 한국식품영양과학회
  41. Abd El-Hack ME, "Microalgae in modern cancer therapy:current knowledge", Biomed. Pharmacother, 111, pp.42~50 (2019)
  42. Saadaoui I, "Algae-derived bioactive compounds with antilung cancer potential", Mar. Drugs, 18, pp.197~ (2020)
  43. Chu TLH, "Cell cycle-dependent tumor engraftment and migration are enabled by aurora-A", Mol. Cancer Res, 16, pp.16~31 (2018)
  44. Fan Z, "Role of the PI3K", AKT pathway in modulating cytoskeleton rearrangements and phenotype switching in rat pulmonary arterial vascular smooth muscle cells, 2014, pp.33, 12~19
  45. Deng S, "PI3K", AKT signaling tips the balance of cytoskeletal forces for cancer progression, 2022, pp.14, 1652~
  46. Thomas D, "Role of tumor and stroma-derived IGF", IGFBPs in pancreatic cancer, 2020, pp.12, 1228~
  47. Jin L, "Insulin growth factor binding protein 7 (IGFBP7)-related cancer and IGFBP3 and IGFBP7crosstalk", Front. Oncol, 10, pp.727~ (2020)
  48. Kerr A, "Noncoding RNA actions through IGFs and IGF binding proteins in cancer", Oncogene, 41, pp.3385~3393 (2020)
  49. Vadlakonda L, "The paradox of Akt-mTOR interactions", Front. Oncol, 3, pp.165~ (2013)
  50. Li W, "Targeting AMPK for cancer prevention and treatment", Oncotarget, 6, pp.7365~7378 (2015)
  51. Inoki K, "TSC2 mediates cellular energy response to control cell growth and survival", Cell, 115, pp.577~590 (2003)
  52. Sook SH, "Reactive oxygen species-mediated activation of AMP-activated protein kinase and c-Jun N-terminal kinase plays a critical role in beta-sitosterol-induced apoptosis in multiple myeloma U266 cells", Phytother. Res, 28, pp.387~394 (2014)
  53. Arul Albert Baskar, "b-Sitosterol Prevents Lipid Peroxidation and Improves Antioxidant Status and Histoarchitecture in Rats with 1,2-Dimethylhydrazine-Induced Colon Cancer", Journal of Medicinal Food, 15(4), pp.335~343 (2012), 한국식품영양과학회[DOI]
  54. Cuyas E, "Cell cycle regulation by the nutrient-sensing mammalian target of rapamycin (mTOR) pathway", Methods Mol. Biol, 1170, pp.113~144 (2014)
  55. Pena-Leon V, "mTOR Pathway is involved in energy homeostasis regulation as a part of the gut-brain axis", Int. J. Mol. Sci, 21, pp.5715~ (2020)
  56. Rojo F, "4E-binding protein 1, a cell signaling hallmark in breast cancer that correlates with pathologic grade and prognosis", Clin. Cancer Res, 13, pp.81~89 (2007)
  57. Khan MI, "The promising future of microalgae: current status, challenges, and optimization of a sustainable and renewable industry for biofuels, feed, and other products", Microb. Cell Fact, 17, pp.36~ (2018)
  58. Wan X, "Effect of marine microalga Chlorella pyrenoidosa ethanol extract on lipid metabolism and gut microbiota composition in high-fat diet-fed rats", Mar. Drugs, 16, pp.498~ (2018)
  59. Arab S, "Chemopreventive effect of spirulina microalgae on an animal model of glioblastoma via down-regulation of PI3K", AKT, miR-125B expression, pp.Phytother. Res, 2021[DOI]
  60. Silva M, "Bioactive compounds of Arthrospira spp. (Spirulina) with potential anticancer activities: a systematic review", ACS Chem. Biol, 16, pp.2057~2067 (2021)
  61. Liao G, "Phycocyanin Inhibits tumorigenic potential of pancreatic cancer cells: role of apoptosis and autophagy", Sci. Rep, 6, pp.34564~ (2016)
  62. Langhans SA, "Three-dimensional in vitro cell culture models in drug discovery and drug repositioning", Front. Pharmacol, 9, pp.6~ (2018)
  63. Jensen C, "Is it time to start transitioning from 2D to 3D cell culture?", Front. Mol. Biosci, 7, pp.33~ (2020)
  64. Schmidt M, "Spheroid-based 3-dimensional culture models: gene expression and functionality in head and neck cancer", Oncol. Rep, 35, pp.2431~2440 (2016)
  65. Na TY, "The functional activity of E-cadherin controls tumor cell metastasis at multiple steps", Proc. Natl. Acad. Sci. USA, 117, pp.5931~5937 (2020)
  66. Cheok CF, "Protecting normal cells from the cytotoxicity of chemotherapy", Cell Cycle, 11, pp.2227~2228 (2012)
  67. Schirrmacher V, "From chemotherapy to biological therapy: a review of novel concepts to reduce the side effects of systemic cancer treatment (Review)", Int. J. Oncol, 54, pp.407~419 (2019)

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