In summary, our study showed that pentadecanoic acid has more specific cytotoxicity in MCF-7/SC than non-stem cell MCF-7 and non-tumorigenic breast epithelial MCF-10A cells. Further, examination exhibited the mechanism that pentadecanoic acid can repress cell proliferation, stem cell properties as well as mobility capacity of the cell by suppressing JAK2/STAT3 signaling. Pentadecanoic acid also accumulated cell cycle arrest and promoted apoptosis in MCF-7/SC cells. This investigation provides the first evidence that pentadecanoic acid has the potential as a novel JAK2/STAT3 inhibitor to target breast cancer cells. Interestingly, pentadecanoic acid enhanced the chemosensitivity of MCF-7/SC cells to tamoxifen, suggesting that pentadecanoic acid has a prominent role in overcoming chemo-resistance, a major clinical challenge, in breast cancer.
REFERENCES
1. Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2016. CA: a cancer journal for clinicians, 2016.
66(1): p. 7-30.
2. Zielske, S.P., et al., Ablation of breast cancer stem cells with radiation. Translational oncology, 2011. 4(4): p.
227.
3. Fillmore, C.M. and C. Kuperwasser, Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast cancer research, 2008. 10(2): p.
R25.
4. Collina, F., et al., Prognostic value of cancer stem cells markers in triple-negative breast cancer. BioMed research international, 2015. 2015.
5. Ginestier, C., et al., ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell stem cell, 2007. 1(5): p. 555-567.
6. Zinzi, L., et al., ABC transporters in CSCs membranes as a novel target for treating tumor relapse. Frontiers in pharmacology, 2014. 5: p. 163.
7. Yang, L., et al., Targeting cancer stem cell pathways for cancer therapy. Signal Transduction and Targeted Therapy, 2020. 5(1): p. 1-35.
8. Galoczova, M., P. Coates, and B. Vojtesek, STAT3, stem cells, cancer stem cells and p63. Cellular &
molecular biology letters, 2018. 23(1): p. 12.
9. Berishaj, M., et al., Stat3 is tyrosine-phosphorylated through the interleukin-6/glycoprotein 130/Janus kinase pathway in breast cancer. Breast Cancer Research, 2007. 9(3): p. R32.
10. McArthur, M.J., et al., Cellular uptake and intracellular trafficking of long chain fatty acids. Journal of lipid research, 1999. 40(8): p. 1371-1383.
11. Caballero, B., L.C. Trugo, and P.M. Finglas, Encyclopedia of food sciences and nutrition. 2003: Academic.
12. Pfeuffer, M. and A. Jaudszus, Pentadecanoic and heptadecanoic acids: multifaceted odd-chain fatty acids.
Advances in Nutrition, 2016. 7(4): p. 730-734.
13. Jenkins, B., J.A. West, and A. Koulman, A review of odd-chain fatty acid metabolism and the role of pentadecanoic acid (C15: 0) and heptadecanoic acid (C17: 0) in health and disease. Molecules, 2015. 20(2): p.
2425-2444.
14. Adamska, A. and J. Rutkowska, Odd-and branched-chain fatty acids in milk fat--characteristic and health properties. Postepy higieny i medycyny doswiadczalnej (Online), 2014. 68: p. 998-1007.
15. Yang, Z., et al., Induction of apoptotic cell death and in vivo growth inhibition of human cancer cells by a saturated branched-chain fatty acid, 13-methyltetradecanoic acid. Cancer research, 2000. 60(3): p. 505-509.
16. Xu, C., et al., Heptadecanoic acid inhibits cell proliferation in PC‑9 non‑small‑cell lung cancer cells with acquired gefitinib resistance. Oncology reports, 2019. 41(6): p. 3499-3507.
17. Nguyen, Y.T.-K., et al., Phenethyl Isothiocyanate Suppresses Stemness in the Chemo-and Radio-Resistant Triple-Negative Breast Cancer Cell Line MDA-MB-231/IR Via Downregulation of Metadherin. Cancers, 2020.
12(2): p. 268.
18. Menendez, J., et al., Oleic acid, the main monounsaturated fatty acid of olive oil, suppresses her-2/neu (erb b-2) expression and synergistically enhances the growth inhibitory effects of trastuzumab (herceptin™) in breast cancer cells with her-2/neu oncogene amplification. Annals of oncology, 2005. 16(3): p. 359-371.
19. Jiang, L., et al., Oleic acid induces apoptosis and autophagy in the treatment of Tongue Squamous cell carcinomas.
Scientific reports, 2017. 7(1): p. 1-11.
20. Moon, H.-S., S. Batirel, and C.S. Mantzoros, Alpha linolenic acid and oleic acid additively down-regulate malignant potential and positively cross-regulate AMPK/S6 axis in OE19 and OE33 esophageal cancer cells.
Metabolism, 2014. 63(11): p. 1447-1454.
21. Lu, X., et al., Linoleic acid suppresses colorectal cancer cell growth by inducing oxidant stress and mitochondrial dysfunction. Lipids in Health and Disease, 2010. 9(1): p. 106.
22. Rahaman, S.O., et al., Inhibition of constitutively active Stat3 suppresses proliferation and induces apoptosis in glioblastoma multiforme cells. Oncogene, 2002. 21(55): p. 8404-8413.
23. Marotta, L.L., et al., The JAK2/STAT3 signaling pathway is required for growth of CD44+ CD24–stem cell–like breast cancer cells in human tumors. The Journal of clinical investigation, 2011. 121(7): p. 2723-2735.
24. Puthier, D., R. Bataille, and M. Amiot, IL‑6 up‑regulates Mcl‑1 in human myeloma cells through JAK/STAT rather than Ras/MAP kinase pathway. European journal of immunology, 1999. 29(12): p. 3945-3950.
25. Ecker, A., et al., The dark and the bright side of Stat3: proto-oncogene and tumor-suppressor. Front Biosci, 2009.
14(1): p. 2944-2958.
26. Chang, R., et al., Loss of Wwox drives metastasis in triple-negative breast cancer by JAK2/STAT3 axis. Nature communications, 2018. 9(1): p. 1-12.
27. Liu, J., et al., GGNBP2 suppresses triple-negative breast cancer aggressiveness through inhibition of IL-6/STAT3 signaling activation. Breast cancer research and treatment, 2019. 174(1): p. 65-78.
28. Pfeffer, C.M. and A.T. Singh, Apoptosis: a target for anticancer therapy. International journal of molecular sciences, 2018. 19(2): p. 448.
29. Christodoulou, M.-I., et al., Nature promises new anticancer agents: Interplay with the apoptosis-related BCL2 gene family. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents), 2014. 14(3): p. 375-399.
30. McLachlan, A., et al., Pancratistatin: a natural anti-cancer compound that targets mitochondria specifically in cancer cells to induce apoptosis. Apoptosis, 2005. 10(3): p. 619-630.
31. von Schwarzenberg, K. and A.M. Vollmar, Targeting apoptosis pathways by natural compounds in cancer:
Marine compounds as lead structures and chemical tools for cancer therapy. Cancer letters, 2013. 332(2): p.
295-303.
32. Kanai, M., et al., Differentiation-inducing factor-1 (DIF-1) inhibits STAT3 activity involved in gastric cancer cell proliferation via MEK-ERK-dependent pathway. Oncogene, 2003. 22(4): p. 548-554.
33. Pancotti, F., et al., Caveolin-1 silencing arrests the proliferation of metastatic lung cancer cells through the inhibition of STAT3 signaling. Cellular signalling, 2012. 24(7): p. 1390-1397.
34. Green, D.R., Apoptotic pathways: the roads to ruin. Cell, 1998. 94(6): p. 695-698.
35. Ayob, A.Z. and T.S. Ramasamy, Cancer stem cells as key drivers of tumour progression. Journal of biomedical science, 2018. 25(1): p. 20.
36. Hardy, S., Y. Langelier, and M. Prentki, Oleate activates phosphatidylinositol 3-kinase and promotes proliferation and reduces apoptosis of MDA-MB-231 breast cancer cells, whereas palmitate has opposite effects1.
Cancer research, 2000. 60(22): p. 6353-6358.
37. Listenberger, L.L., D.S. Ory, and J.E. Schaffer, Palmitate-induced apoptosis can occur through a ceramide-independent pathway. Journal of Biological Chemistry, 2001. 276(18): p. 14890-14895.
38. Mu, Y.-M., et al., Saturated FFAs, palmitic acid and stearic acid, induce apoptosis in human granulosa cells.
Endocrinology, 2001. 142(8): p. 3590-3597.
39. Zhang, Y., et al., Palmitic and linoleic acids induce ER stress and apoptosis in hepatoma cells. Lipids in health and disease, 2012. 11(1): p. 1.
40. Evans, L.M., et al., Stearate preferentially induces apoptosis in human breast cancer cells. Nutrition and cancer, 2009. 61(5): p. 746-753.
41. Hardy, S., et al., Saturated fatty acid-induced apoptosis in mda-mb-231 breast cancer cells a role for cardiolipin.
Journal of Biological Chemistry, 2003. 278(34): p. 31861-31870.
42. De Angelis, M.L., F. Francescangeli, and A. Zeuner, Breast Cancer Stem Cells as Drivers of Tumor Chemoresistance, Dormancy and Relapse: New Challenges and Therapeutic Opportunities. Cancers, 2019.
11(10): p. 1569.
43. Wang, L., et al., The role of CD44 and cancer stem cells, in Cancer Stem Cells. 2018, Springer. p. 31-42.
44. Nieto, M.A., Epithelial plasticity: a common theme in embryonic and cancer cells. Science, 2013. 342(6159): p.
1234850.
45. Nieto, M.A., et al., EMT: 2016. Cell, 2016. 166(1): p. 21-45.
46. Varga, J. and F.R. Greten, Cell plasticity in epithelial homeostasis and tumorigenesis. Nature cell biology, 2017. 19(10): p. 1133-1141.
47. Mani, S.A., et al., The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell, 2008.
133(4): p. 704-715.
48. Liu, S., et al., Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem cell reports, 2014. 2(1): p. 78-91.
49. Gilles, C., et al., Matrix Metalloproteases and Epithelial-to-Mesenchymal Transition, in Rise and Fall of Epithelial Phenotype. 2005, Springer. p. 297-315.
50. Egeblad, M. and Z. Werb, New functions for the matrix metalloproteinases in cancer progression. Nature Reviews Cancer, 2002. 2(3): p. 161-174.
51. Sternlicht, M.D. and Z. Werb, How matrix metalloproteinases regulate cell behavior. Annual review of cell and developmental biology, 2001. 17(1): p. 463-516.
52. Wang, B., et al., Expression and significance of MMP2 and HIF‑1α in hepatocellular carcinoma. Oncology letters, 2014. 8(2): p. 539-546.
53. Heissig, B., et al., Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell, 2002. 109(5): p. 625-637.
54. Ganesan, R., E. Mallets, and J. Gomez-Cambronero, The transcription factors Slug (SNAI2) and Snail (SNAI1) regulate phospholipase D (PLD) promoter in opposite ways towards cancer cell invasion. Molecular oncology, 2016. 10(5): p. 663-676.
55. Banerjee, K. and H. Resat, Constitutive activation of STAT 3 in breast cancer cells: A review. International journal of cancer, 2016. 138(11): p. 2570-2578.
56. Song, H., et al., A low-molecular-weight compound discovered through virtual database screening inhibits Stat3 function in breast cancer cells. Proceedings of the National Academy of Sciences, 2005. 102(13): p. 4700-4705.
57. Kortylewski, M., R. Jove, and H. Yu, Targeting STAT3 affects melanoma on multiple fronts. Cancer and Metastasis Reviews, 2005. 24(2): p. 315-327.
61. Siveen, K.S., et al., Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors.
Biochimica et Biophysica Acta (BBA)-reviews on cancer, 2014. 1845(2): p. 136-154.
62. Lin, L., et al., STAT3 is necessary for proliferation and survival in colon cancer–initiating cells. Cancer research, 2011. 71(23): p. 7226-7237.
63. Corvinus, F.M., et al., Persistent STAT3 activation in colon cancer is associated with enhanced cell proliferation and tumor growth. Neoplasia (New York, NY), 2005. 7(6): p. 545.
64. Xie, T.-x., et al., Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis. Oncogene, 2004. 23(20): p. 3550-3560.
65. Yang, J., et al., Novel roles of unphosphorylated STAT3 in oncogenesis and transcriptional regulation. Cancer research, 2005. 65(3): p. 939-947.
66. Yang, J. and G.R. Stark, Roles of unphosphorylated STATs in signaling. Cell research, 2008. 18(4): p. 443-451.
67. Zegeye, M.M., et al., Activation of the JAK/STAT3 and PI3K/AKT pathways are crucial for IL-6 trans-signaling-mediated pro-inflammatory response in human vascular endothelial cells. Cell Communication and Signaling, 2018. 16(1): p. 1-10.
68. Hirano, T., K. Ishihara, and M. Hibi, Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene, 2000. 19(21): p. 2548-2556.
69. Xie, Q., et al., Ilamycin C induces apoptosis and inhibits migration and invasion in triple-negative breast cancer by suppressing IL-6/STAT3 pathway. Journal of hematology & oncology, 2019. 12(1): p. 60.
70. McIlwain, D.R., T. Berger, and T.W. Mak, Caspase functions in cell death and disease. Cold Spring Harbor perspectives in biology, 2013. 5(4): p. a008656.
71. Parrish, A.B., C.D. Freel, and S. Kornbluth, Cellular mechanisms controlling caspase activation and function.
Cold Spring Harbor perspectives in biology, 2013. 5(6): p. a008672.
72. Wolf, B.B. and D.R. Green, Suicidal tendencies: apoptotic cell death by caspase family proteinases. Journal of Biological Chemistry, 1999. 274(29): p. 20049-20052.
73. Chaitanya, G.V., J.S. Alexander, and P.P. Babu, PARP-1 cleavage fragments: signatures of cell-death proteases in neurodegeneration. Cell Communication and Signaling, 2010. 8(1): p. 31.
74. Ali, S., et al., Molecular mechanisms and mode of tamoxifen resistance in breast cancer. Bioinformation, 2016.
12(3): p. 135.
75. Moon, J.Y., et al., Nobiletin enhances chemosensitivity to adriamycin through modulation of the Akt/GSK3β/β–
catenin/MYCN/MRP1 signaling pathway in A549 human non-small-cell lung cancer cells. Nutrients, 2018.
10(12): p. 1829.