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Strigolactones: a novel class of phytohormones that inhibit the growth and survival of breast cancer cells and breast cancer stem-like enriched mammosphere cells

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Abstract

Several naturally occurring phytohormones have shown enormous potential in the prevention and treatment of variety of different type of cancers. Strigolactones (SLs) are a novel class of plant hormones produced in roots and regulate new above ground shoot branching, by inhibiting self-renewal of undifferentiated meristem cells. Here, we study the effects of six synthetic SL analogs on breast cancer cell lines growth and survival. We show that SL analogs are able to inhibit proliferation and induce apoptosis of breast cancer cells but to a much lesser extent “non-cancer” lines. Given the therapeutic problem of cancer recurrence which is hypothesized to be due to drug resistant cancer stem cells, we also tested the ability of SL analogs to inhibit the growth of mammosphere cultures that are typically enriched with cancer stem-like cells. We show that SLs are potent inhibitors of self-renewal and survival of breast cancer cell lines grown as mammospheres and even a short exposure leads to irreversible effects on mammosphere dissociation and cell death. Immunoblot analysis revealed that SLs analogs induce activation of the stress response mediated by both P38 and JNK1/2 MAPK modules and inhibits PI3K/AKT activation. Taken together this study indicates that SLs may be promising anticancer agents whose activities may be achieved through modulation of stress and survival signaling pathways.

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Abbreviations

SL:

Strigolactone

CSC:

Cancer stem cell

ppm:

Parts per million

PI:

Propidium iodide

ERK:

Extracellular signal-regulated kinase

p38 MAPK:

p38 mitogen-activated protein kinase

MSK1:

Mitogen- and stress-activated protein kinase

ATF2:

Activating transcription factor 2

AKT:

Protein kinase B

IC:

Inhibitory concentration

References

  1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127:2893–2917

    Article  PubMed  CAS  Google Scholar 

  2. Newman DJ, Cragg GM (2004) Advanced preclinical and clinical trials of natural products and related compounds from marine sources. Curr Med Chem 11:1693–1713

    PubMed  CAS  Google Scholar 

  3. Skoog F, Strong FM, Miller CO (1965) Cytokinins. Science 148:532–533

    Article  PubMed  CAS  Google Scholar 

  4. Ishii Y, Sakai S, Honma Y (2003) Cytokinin-induced differentiation of human myeloid leukemia HL-60 cells is associated with the formation of nucleotides, but not with incorporation into DNA or RNA. Biochim Biophys Acta 1643:11–24

    Article  PubMed  CAS  Google Scholar 

  5. Mlejnek P (2001) Caspase inhibition and N6-benzyladenosine-induced apoptosis in HL-60 cells. J Cell Biochem 83:678–689

    Article  PubMed  CAS  Google Scholar 

  6. Mlejnek P (2001) Caspase-3 activity and carbonyl cyanide m-chlorophenylhydrazone-induced apoptosis in HL-60. Altern Lab Anim 29:243–249

    PubMed  CAS  Google Scholar 

  7. Cohen S, Flescher E (2009) Methyl jasmonate: a plant stress hormone as an anti-cancer drug. Phytochemistry 70:1600–1609

    Article  PubMed  CAS  Google Scholar 

  8. Goldin N, Arzoine L, Heyfets A, Israelson A, Zaslavsky Z, Bravman T, Bronner V, Notcovich A, Shoshan-Barmatz V, Flescher E (2008) Methyl jasmonate binds to and detaches mitochondria-bound hexokinase. Oncogene 27:4636–4643

    Article  PubMed  CAS  Google Scholar 

  9. Elia U, Flescher E (2008) PI3K/Akt pathway activation attenuates the cytotoxic effect of methyl jasmonate toward sarcoma cells. Neoplasia 10:1303–1313

    PubMed  CAS  Google Scholar 

  10. Oh SY, Kim JH, Park MJ, Kim SM, Yoon CS, Joo YM, Park JS, Han SI, Park HG, Kang HS (2005) Induction of heat shock protein 72 in C6 glioma cells by methyl jasmonate through ROS-dependent heat shock factor 1 activation. Int J Mol Med 16:833–839

    PubMed  CAS  Google Scholar 

  11. Clouse SD, Sasse JM (1998) Brassinosteroids: essential regulators of plant growth and development. Annu Rev Plant Physiol Plant Mol Biol 49:427–451

    Article  PubMed  CAS  Google Scholar 

  12. Steigerova J, Oklestkova J, Levkova M, Rarova L, Kolar Z, Strnad M (2010) Brassinosteroids cause cell cycle arrest and apoptosis of human breast cancer cells. Chem Biol Interact 188:487–496

    Article  PubMed  CAS  Google Scholar 

  13. Xie X, Yoneyama K (2010) The strigolactone story. Annu Rev Phytopathol 48:93–117

    Article  PubMed  CAS  Google Scholar 

  14. Akiyama K, Ogasawara S, Ito S, Hayashi H (2010) Structural requirements of strigolactones for hyphal branching in AM fungi. Plant Cell Physiol 51:1104–1117

    Article  PubMed  CAS  Google Scholar 

  15. Kapulnik Y, Delaux PM, Resnick N, Mayzlish-Gati E, Wininger S, Bhattacharya C, Sejalon-Delmas N, Combier JP, Becard G, Belausov E, Beeckman T, Dor E, Hershenhorn J, Koltai H (2011) Strigolactones affect lateral root formation and root-hair elongation in Arabidopsis. Planta 233:209–216

    Article  PubMed  CAS  Google Scholar 

  16. Rameau C (2010) Strigolactones, a novel class of plant hormone controlling shoot branching. C R Biol 333:344–349

    Article  PubMed  CAS  Google Scholar 

  17. Gomez-Roldan V, Fermas S, Brewer PB, Puech-Pages V, Dun EA, Pillot JP, Letisse F, Matusova R, Danoun S, Portais JC, Bouwmeester H, Becard G, Beveridge CA, Rameau C, Rochange SF (2008) Strigolactone inhibition of shoot branching. Nature 455:189–194

    Article  PubMed  CAS  Google Scholar 

  18. Umehara M, Hanada A, Yoshida S, Akiyama K, Arite T, Takeda-Kamiya N, Magome H, Kamiya Y, Shirasu K, Yoneyama K, Kyozuka J, Yamaguchi S (2008) Inhibition of shoot branching by new terpenoid plant hormones. Nature 455:195–200

    Article  PubMed  CAS  Google Scholar 

  19. Sharma VK, Fletcher JC (2002) Maintenance of shoot and floral meristem cell proliferation and fate. Plant Physiol 129:31–39

    Article  PubMed  CAS  Google Scholar 

  20. Koltai H, Dor E, Hershenhorn J, Daniel M, Weininger S, Lekalla S, Shealtiel H, Bhattacharya C, Eliahu E, Resnick N, Barg R, Kapulnik Y (2010) Strigolactones’ effect on root growth and root-hair elongation may be mediated by auxin-efflux carriers. J Plant Growth Regul 29:129–136

    Article  CAS  Google Scholar 

  21. Dor E, Joel DM, Kapulnik Y, Koltai H, Hershenhorn J (2011) The synthetic strigolactone GR24 influences the growth pattern of phytopathogenic fungi. Planta 234:419–427

    Article  PubMed  CAS  Google Scholar 

  22. Bhattacharya C, Bonfante P, Deagostino A, Kapulnik Y, Larini P, Occhiato EG, Prandi C, Venturello P (2009) A new class of conjugated strigolactone analogues with fluorescent properties: synthesis and biological activity. Org Biomol Chem 7:3413–3420

    Article  PubMed  CAS  Google Scholar 

  23. Mwakaboko AS, Zwanenburg B (2011) Single step synthesis of strigolactone analogues from cyclic keto enols, germination stimulants for seeds of parasitic weeds. Bioorg Med Chem 19:5006–5011

    Article  PubMed  CAS  Google Scholar 

  24. Dontu G, Abdallah WM, Foley JM, Jackson KW, Clarke MF, Kawamura MJ, Wicha MS (2003) In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev 17:1253–1270

    Article  PubMed  CAS  Google Scholar 

  25. Prud’homme GJ, Glinka Y, Toulina A, Ace O, Subramaniam V, Jothy S (2010) Breast cancer stem-like cells are inhibited by a non-toxic aryl hydrocarbon receptor agonist. PLoS One 5:e13831

    Article  PubMed  Google Scholar 

  26. Singh A, Settleman J (2010) EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29:4741–4751

    Article  PubMed  CAS  Google Scholar 

  27. Charafe-Jauffret E, Ginestier C, Iovino F, Wicinski J, Cervera N, Finetti P, Hur MH, Diebel ME, Monville F, Dutcher J, Brown M, Viens P, Xerri L, Bertucci F, Stassi G, Dontu G, Birnbaum D, Wicha MS (2009) Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res 69:1302–1313

    Article  PubMed  CAS  Google Scholar 

  28. Cariati M, Naderi A, Brown JP, Smalley MJ, Pinder SE, Caldas C, Purushotham AD (2008) Alpha-6 integrin is necessary for the tumourigenicity of a stem cell-like subpopulation within the MCF7 breast cancer cell line. Int J Cancer 122:298–304

    Article  PubMed  CAS  Google Scholar 

  29. Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF, Hilsenbeck SG, Pavlick A, Zhang X, Chamness GC, Wong H, Rosen J, Chang JC (2008) Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 100:672–679

    Article  PubMed  CAS  Google Scholar 

  30. Jiang F, Qiu Q, Khanna A, Todd NW, Deepak J, Xing L, Wang H, Liu Z, Su Y, Stass SA, Katz RL (2009) Aldehyde dehydrogenase 1 is a tumor stem cell-associated marker in lung cancer. Mol Cancer Res 7:330–338

    Article  PubMed  CAS  Google Scholar 

  31. Burger PE, Gupta R, Xiong X, Ontiveros CS, Salm SN, Moscatelli D, Wilson EL (2009) High aldehyde dehydrogenase activity: a novel functional marker of murine prostate stem/progenitor cells. Stem Cells 27:2220–2228

    Article  PubMed  CAS  Google Scholar 

  32. Croker AK, Goodale D, Chu J, Postenka C, Hedley BD, Hess DA, Allan AL (2009) High aldehyde dehydrogenase and expression of cancer stem cell markers selects for breast cancer cells with enhanced malignant and metastatic ability. J Cell Mol Med 13:2236–2252

    Article  PubMed  Google Scholar 

  33. Cuadrado A, Nebreda AR (2010) Mechanisms and functions of p38 MAPK signalling. Biochem J 429:403–417

    Article  PubMed  CAS  Google Scholar 

  34. Saccani S, Pantano S, Natoli G (2002) p38-dependent marking of inflammatory genes for increased NF-kappa B recruitment. Nat Immunol 3:69–75

    Article  PubMed  CAS  Google Scholar 

  35. Deak M, Clifton AD, Lucocq LM, Alessi DR (1998) Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB. EMBO J 17:4426–4441

    Article  PubMed  CAS  Google Scholar 

  36. Cargnello M, Roux PP (2011) Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev 75:50–83

    Article  PubMed  CAS  Google Scholar 

  37. Gum RJ, Young PR (1999) Identification of two distinct regions of p38 MAPK required for substrate binding and phosphorylation. Biochem Biophys Res Commun 266:284–289

    Article  PubMed  CAS  Google Scholar 

  38. Bhoumik A, Lopez-Bergami P, Ronai Z (2007) ATF2 on the double-activating transcription factor and DNA damage response protein. Pigment Cell Res 20:498–506

    Article  PubMed  CAS  Google Scholar 

  39. Gong G, Stern HS, Cheng SC, Fong N, Mordeson J, Deng HW, Recker RR (1999) The association of bone mineral density with vitamin D receptor gene polymorphisms. Osteoporos Int 9:55–64

    Article  PubMed  CAS  Google Scholar 

  40. Woodgett JR (2005) Recent advances in the protein kinase B signaling pathway. Curr Opin Cell Biol 17:150–157

    Article  PubMed  CAS  Google Scholar 

  41. Scheid MP, Marignani PA, Woodgett JR (2002) Multiple phosphoinositide 3-kinase-dependent steps in activation of protein kinase B. Mol Cell Biol 22:6247–6260

    Article  PubMed  CAS  Google Scholar 

  42. Shaw M, Cohen P, Alessi DR (1997) Further evidence that the inhibition of glycogen synthase kinase-3beta by IGF-1 is mediated by PDK1/PKB-induced phosphorylation of Ser-9 and not by dephosphorylation of Tyr-216. FEBS Lett 416:307–311

    Article  PubMed  CAS  Google Scholar 

  43. Casamayor A, Morrice NA, Alessi DR (1999) Phosphorylation of Ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1: identification of five sites of phosphorylation in vivo. Biochem J 342(Pt 2):287–292

    Article  PubMed  CAS  Google Scholar 

  44. Correze C, Blondeau JP, Pomerance M (2005) p38 mitogen-activated protein kinase contributes to cell cycle regulation by cAMP in FRTL-5 thyroid cells. Eur J Endocrinol 153:123–133

    Article  PubMed  CAS  Google Scholar 

  45. Iyoda K, Sasaki Y, Horimoto M, Toyama T, Yakushijin T, Sakakibara M, Takehara T, Fujimoto J, Hori M, Wands JR, Hayashi N (2003) Involvement of the p38 mitogen-activated protein kinase cascade in hepatocellular carcinoma. Cancer 97:3017–3026

    Article  PubMed  CAS  Google Scholar 

  46. Chang HL, Wu YC, Su JH, Yeh YT, Yuan SS (2008) Protoapigenone, a novel flavonoid, induces apoptosis in human prostate cancer cells through activation of p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase 1/2. J Pharmacol Exp Ther 325:841–849

    Article  PubMed  CAS  Google Scholar 

  47. She QB, Chen N, Dong Z (2000) ERKs and p38 kinase phosphorylate p53 protein at serine 15 in response to UV radiation. J Biol Chem 275:20444–20449

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We gratefully thank Drs. Rebecca Riggins, York Tomita, and Michael Johnson (Lombardi Cancer Centre) for sharing reagents and helpful discussion. We thank the flow cytometry core facility at Lombardi Cancer Center for assistance with the cell cycle analysis. This study was supported by the Department of Defense Breast Program W81XWH-11-1-0190 (RIY) and by the BioBits Project, Regione Piemonte, Italy (CP).

Conflict of interest

The authors declare that there is no conflict of interests.

Author information

Authors and Affiliations

  1. Department of Human Science, Georgetown University, St. Mary’s Hall Rm 260, Washington, DC, 20007, USA

    C. B. Pollock & R. I. Yarden

  2. Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3700 Reservoir Road, NW, Washington, DC, 20057, USA

    C. B. Pollock & R. I. Yarden

  3. Department of Ornamental Horticulture, Agricultural Research Organization (ARO), The Volcani Center, PO Box 6, 50250, Bet Dagan, Israel

    H. Koltai

  4. Department of Field Crops and Natural Resources Institute of Plant Sciences, Agricultural Research Organization (ARO), The Volcani Center, PO Box 6, 50250, Bet Dagan, Israel

    Y. Kapulnik

  5. Department of Chemistry, University Turin, via P. Giuria 7, 10125, Turin, Italy

    C. Prandi

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  1. C. B. Pollock
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Correspondence to R. I. Yarden.

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Pollock, C.B., Koltai, H., Kapulnik, Y. et al. Strigolactones: a novel class of phytohormones that inhibit the growth and survival of breast cancer cells and breast cancer stem-like enriched mammosphere cells. Breast Cancer Res Treat 134, 1041–1055 (2012). https://doi.org/10.1007/s10549-012-1992-x

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