Advertisement

Cancer Chemotherapy and Pharmacology

, Volume 73, Issue 4, pp 711–719 | Cite as

Perifosine inhibits S6K1–Gli1 signaling and enhances gemcitabine-induced anti-pancreatic cancer efficiency

  • Ying Xin
  • Xiang-di Shen
  • Long ChengEmail author
  • De-fei Hong
  • Bin ChenEmail author
Original Article

Abstract

Purpose

The pancreatic cancer has extremely low overall 5-year survival, and gemcitabine is the only approved single agent for pancreatic cancer treatment.

Methods

In the present study, we investigated the potential effect of perifosine, a novel Akt inhibitor on gemcitabine-induced anti-pancreatic cancer effect both in vivo and in vitro.

Results

We showed that sub-cytotoxic low concentration of perifosine dramatically enhanced gemcitabine-induced cytotoxicity in cultured pancreatic cancer cells. Perifosine inhibited Akt–mammalian target of rapamycin and Erk–mitogen-activated protein kinase activation in pancreatic cancer cells. Meanwhile, perifosine suppressed the hedgehog signaling, as it inhibited glioma-associated oncogenes (Gli) 1 activation and decreased its target protein patched 1 (PTCH1) expression. Our data demonstrated that perifosine blocked p70S6K1 (S6K1) activation, thus disrupting S6K1–Gli1 association and subsequent Gli1 activation. The reduction of S6K1 or Gli1 expression by target siRNAs inhibited PTCH1 expression and enhanced gemcitabine-induced cytotoxicity in pancreatic cancer cells. Significantly, perifosine dramatically enhanced gemcitabine-mediated antitumor effect in a PANC-1 xenograft severe combined immunodeficiency mice model.

Conclusions

In summary, we conclude that perifosine sensitizes gemcitabine-mediated anti-pancreatic cancer efficiency through regulating multiple signaling pathways.

Keywords

The pancreatic cancer Perifosine Gemcitabine Akt–mTOR Hh–Gli signaling 

Abbreviations

Gli

Glioma-associated oncogenes

mTOR

Mammalian target of rapamycin

MAPK

Mitogen-activated protein kinase

Hh

Hedgehog

CCK-8

Cell counting kit-8

SMO

Smoothened

Sufu

Suppressor of fused

PTCH1

Patched 1

Notes

Acknowledgments

This work was supported by the talent plan of Science and Technology Bureau of Zhejiang Province (2012R10043). The founders have no roles in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

Conflict of interest

No conflict of interests are stated.

References

  1. 1.
    Stathis A, Moore MJ (2010) Advanced pancreatic carcinoma: current treatment and future challenges. Nat Rev Clin Oncol 7(3):163–172Google Scholar
  2. 2.
    Schneider G, Siveke JT, Eckel F, Schmid RM (2005) Pancreatic cancer: basic and clinical aspects. Gastroenterology 128(6):1606–1625PubMedCrossRefGoogle Scholar
  3. 3.
    Gudjonsson B (2009) Pancreatic cancer: survival, errors and evidence. Eur J Gastroenterol Hepatol 21(12):1379–1382PubMedCrossRefGoogle Scholar
  4. 4.
    Wray CJ, Ahmad SA, Matthews JB, Lowy AM (2005) Surgery for pancreatic cancer: recent controversies and current practice. Gastroenterology 128(6):1626–1641PubMedCrossRefGoogle Scholar
  5. 5.
    Lockhart AC, Rothenberg ML, Berlin JD (2005) Treatment for pancreatic cancer: current therapy and continued progress. Gastroenterology 128(6):1642–1654PubMedCrossRefGoogle Scholar
  6. 6.
    Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H (2007) Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA 297(3):267–277PubMedCrossRefGoogle Scholar
  7. 7.
    Rivera F, Lopez-Tarruella S, Vega-Villegas ME, Salcedo M (2009) Treatment of advanced pancreatic cancer: from gemcitabine single agent to combinations and targeted therapy. Cancer Treat Rev 35(4):335–339PubMedCrossRefGoogle Scholar
  8. 8.
    Westphal S, Kalthoff H (2003) Apoptosis: targets in pancreatic cancer. Mol Cancer 2:6PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Gills JJ, Dennis PA (2009) Perifosine: update on a novel Akt inhibitor. Curr Oncol Rep 11(2):102–110PubMedCrossRefGoogle Scholar
  10. 10.
    Kondapaka SB, Singh SS, Dasmahapatra GP, Sausville EA, Roy KK (2003) Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation. Mol Cancer Ther 2(11):1093–1103PubMedGoogle Scholar
  11. 11.
    Richardson PG, Wolf J, Jakubowiak A, Zonder J, Lonial S, Irwin D, Densmore J, Krishnan A, Raje N, Bar M, Martin T, Schlossman R, Ghobrial IM, Munshi N, Laubach J, Allerton J, Hideshima T, Colson K, Poradosu E, Gardner L, Sportelli P, Anderson KC (2011) Perifosine plus bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma previously treated with bortezomib: results of a multicenter phase I/II trial. J Clin Oncol 29(32):4243–4249PubMedCrossRefGoogle Scholar
  12. 12.
    Bendell JC, Nemunaitis J, Vukelja SJ, Hagenstad C, Campos LT, Hermann RC, Sportelli P, Gardner L, Richards DA (2011) Randomized placebo-controlled phase II trial of perifosine plus capecitabine as second- or third-line therapy in patients with metastatic colorectal cancer. J Clin Oncol 29(33):4394–4400PubMedCrossRefGoogle Scholar
  13. 13.
    Ruiz i Altaba A, Sanchez P, Dahmane N (2002) Gli and hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer 2(5):361–372PubMedCrossRefGoogle Scholar
  14. 14.
    Yauch RL, Gould SE, Scales SJ, Tang T, Tian H, Ahn CP, Marshall D, Fu L, Januario T, Kallop D, Nannini-Pepe M, Kotkow K, Marsters JC, Rubin LL, de Sauvage FJ (2008) A paracrine requirement for hedgehog signalling in cancer. Nature 455(7211):406–410PubMedCrossRefGoogle Scholar
  15. 15.
    Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY, Qi YP, Gysin S, Fernandez-del Castillo C, Yajnik V, Antoniu B, McMahon M, Warshaw AL, Hebrok M (2003) Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425(6960):851–856PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Pasca di Magliano M, Hebrok M (2003) Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer 3(12):903–911PubMedCrossRefGoogle Scholar
  17. 17.
    Taipale J, Beachy PA (2001) The hedgehog and Wnt signalling pathways in cancer. Nature 411(6835):349–354PubMedCrossRefGoogle Scholar
  18. 18.
    Feldmann G, Dhara S, Fendrich V, Bedja D, Beaty R, Mullendore M, Karikari C, Alvarez H, Iacobuzio-Donahue C, Jimeno A, Gabrielson KL, Matsui W, Maitra A (2007) Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res 67(5):2187–2196PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Rubin LL, de Sauvage FJ (2006) Targeting the hedgehog pathway in cancer. Nat Rev Drug Discov 5(12):1026–1033PubMedCrossRefGoogle Scholar
  20. 20.
    Wang Y, Ding Q, Yen CJ, Xia W, Izzo JG, Lang JY, Li CW, Hsu JL, Miller SA, Wang X, Lee DF, Hsu JM, Huo L, Labaff AM, Liu D, Huang TH, Lai CC, Tsai FJ, Chang WC, Chen CH, Wu TT, Buttar NS, Wang KK, Wu Y, Wang H, Ajani J, Hung MC (2012) The crosstalk of mTOR/S6K1 and hedgehog pathways. Cancer Cell 21(3):374–387PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Stecca B, Mas C, Clement V, Zbinden M, Correa R, Piguet V, Beermann F, Ruiz IAA (2007) Melanomas require HEDGEHOG–GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways. Proc Natl Acad Sci USA 104(14):5895–5900PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Seto M, Ohta M, Asaoka Y, Ikenoue T, Tada M, Miyabayashi K, Mohri D, Tanaka Y, Ijichi H, Tateishi K, Kanai F, Kawabe T, Omata M (2009) Regulation of the hedgehog signaling by the mitogen-activated protein kinase cascade in gastric cancer. Mol Carcinog 48(8):703–712PubMedCrossRefGoogle Scholar
  23. 23.
    Wan X, Harkavy B, Shen N, Grohar P, Helman LJ (2007) Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene 26(13):1932–1940PubMedCrossRefGoogle Scholar
  24. 24.
    Sanchez P, Hernandez AM, Stecca B, Kahler AJ, DeGueme AM, Barrett A, Beyna M, Datta MW, Datta S, Ruiz i Altaba A (2004) Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG–GLI1 signaling. Proc Natl Acad Sci USA 101(34):12561–12566PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Parsons CM, Muilenburg D, Bowles TL, Virudachalam S, Bold RJ (2010) The role of Akt activation in the response to chemotherapy in pancreatic cancer. Anticancer Res 30(9):3279–3289PubMedGoogle Scholar
  26. 26.
    Shin-Kang S, Ramsauer VP, Lightner J, Chakraborty K, Stone W, Campbell S, Reddy SA, Krishnan K (2011) Tocotrienols inhibit AKT and ERK activation and suppress pancreatic cancer cell proliferation by suppressing the ErbB2 pathway. Free Radic Biol Med 51(6):1164–1174PubMedCrossRefGoogle Scholar
  27. 27.
    Garrido-Laguna I, Tan AC, Uson M, Angenendt M, Ma WW, Villaroel MC, Zhao M, Rajeshkumar NV, Jimeno A, Donehower R, Iacobuzio-Donahue C, Barrett M, Rudek MA, Rubio-Viqueira B, Laheru D, Hidalgo M (2010) Integrated preclinical and clinical development of mTOR inhibitors in pancreatic cancer. Br J Cancer 103(5):649–655PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Roy SK, Srivastava RK, Shankar S (2010) Inhibition of PI3 K/AKT and MAPK/ERK pathways causes activation of FOXO transcription factor, leading to cell cycle arrest and apoptosis in pancreatic cancer. J Mol Signal 5:10PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Costello E, Neoptolemos JP (2011) Pancreatic cancer in 2010: new insights for early intervention and detection. Nat Rev Gastroenterol Hepatol 8(2):71–73PubMedCrossRefGoogle Scholar
  30. 30.
    Heinemann V, Boeck S, Hinke A, Labianca R, Louvet C (2008) Meta-analysis of randomized trials: evaluation of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer. BMC Cancer 8:82PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the national cancer institute of Canada clinical trials group. J Clin Oncol 25(15):1960–1966PubMedCrossRefGoogle Scholar
  32. 32.
    Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB (2005) Exploiting the PI3 K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 4(12):988–1004PubMedCrossRefGoogle Scholar
  33. 33.
    Tanno S, Mitsuuchi Y, Altomare DA, Xiao GH, Testa JR (2001) AKT activation up-regulates insulin-like growth factor I receptor expression and promotes invasiveness of human pancreatic cancer cells. Cancer Res 61(2):589–593PubMedGoogle Scholar
  34. 34.
    Azzariti A, Porcelli L, Gatti G, Nicolin A, Paradiso A (2008) Synergic antiproliferative and antiangiogenic effects of EGFR and mTOR inhibitors on pancreatic cancer cells. Biochem Pharmacol 75(5):1035–1044PubMedCrossRefGoogle Scholar
  35. 35.
    Wolpin BM, Hezel AF, Abrams T, Blaszkowsky LS, Meyerhardt JA, Chan JA, Enzinger PC, Allen B, Clark JW, Ryan DP, Fuchs CS (2009) Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer. J Clin Oncol 27(2):193–198PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Elrod HA, Lin YD, Yue P, Wang X, Lonial S, Khuri FR, Sun SY (2007) The alkylphospholipid perifosine induces apoptosis of human lung cancer cells requiring inhibition of Akt and activation of the extrinsic apoptotic pathway. Mol Cancer Ther 6(7):2029–2038PubMedCrossRefGoogle Scholar
  37. 37.
    Ji C, Yang YL, Yang Z, Tu Y, Cheng L, Chen B, Xia JP, Sun WL, Su ZL, He L, Bi ZG (2012) Perifosine sensitizes UVB-induced apoptosis in skin cells: new implication of skin cancer prevention? Cell Signal 24(9):1781–1789PubMedCrossRefGoogle Scholar
  38. 38.
    Coni S, Infante P, Gulino A (2013) Control of stem cells and cancer stem cells by hedgehog signaling: pharmacologic clues from pathway dissection. Biochem Pharmacol 85(5):623–628PubMedCrossRefGoogle Scholar
  39. 39.
    Metcalfe C, de Sauvage FJ (2011) Hedgehog fights back: mechanisms of acquired resistance against Smoothened antagonists. Cancer Res 71(15):5057–5061PubMedCrossRefGoogle Scholar
  40. 40.
    Buonamici S, Williams J, Morrissey M, Wang A, Guo R, Vattay A, Hsiao K, Yuan J, Green J, Ospina B, Yu Q, Ostrom L, Fordjour P, Anderson DL, Monahan JE, Kelleher JF, Peukert S, Pan S, Wu X, Maira SM, GarciaEcheverria C, Briggs KJ, Watkins DN, Yao YM, Lengauer C, Warmuth M, Sellers WR, Dorsch M (2010) Interfering with resistance to smoothened antagonists by inhibition of the PI3 K pathway in medulloblastoma. Sci Transl Med 2 (51): 51ra70Google Scholar
  41. 41.
    Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell 12(1):9–22PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of Thyroid and Breast SurgeryZhejiang Provincial People’s HospitalHangzhouChina
  2. 2.Office of ResearchZhejiang Medical CollegeHangzhouChina
  3. 3.Department of Interventional RadiologyThe Second Affiliated Hospital of Soochow UniversitySuzhouChina
  4. 4.Department of Hepatobiliary SurgeryZhejiang Provincial People’s HospitalHangzhouChina
  5. 5.Department of General SurgeryNo.1 People’s Hospital of HangzhouHangzhouChina

Personalised recommendations