Phycocyanin Inhibits Tumorigenic Potential of Pancreatic Cancer Cells: Role of Apoptosis and Autophagy.
Pancreatic adenocarcinoma (PDA) is one of the most lethal human malignancies, and unresponsive to current chemotherapies. Here we investigate the therapeutic potential of phycocyanin as an anti-PDA agent in vivo and in vitro. Phycocyanin, a natural product purified from Spirulina, effectively inhibits the pancreatic cancer cell proliferation in vitro and xenograft tumor growth in vivo. Phycocyanin induces G2/M cell cycle arrest, apoptotic and autophagic cell death in PANC-1 cells. Inhibition of autophagy by targeting Beclin 1 using siRNA significantly suppresses cell growth inhibition and death induced by phycocyanin, whereas inhibition of both autophagy and apoptosis rescues phycocyanin-mediated cell death. Mechanistically, cell death induced by phycocyanin is the result of cross-talk among the MAPK, Akt/mTOR/p70S6K and NF-κB pathways. Phycocyanin is able to induce apoptosis of PANC-1 cell by activating p38 and JNK signaling pathways while inhibiting Erk pathway. On the other hand, phycocyanin promotes autophagic cell death by inhibiting PI3/Akt/mTOR signaling pathways. Furthermore, phycocyanin promotes the activation and nuclear translocation of NF-κB, which plays an important role in balancing phycocyanin-mediated apoptosis and autosis. In conclusion, our studies demonstrate that phycocyanin exerts anti-pancreatic cancer activity by inducing apoptotic and autophagic cell death, thereby identifying phycocyanin as a promising anti-pancreatic cancer agent.
School of Life Science &Technology, China Pharmaceutical University, Nanjing, China.
Gaoyong
G
Liao
School of Life Science &Technology, China Pharmaceutical University, Nanjing, China.
Bing
B
Gao
School of Life Science &Technology, China Pharmaceutical University, Nanjing, China.
Yingnv
Y
Gao
School of Life Science &Technology, China Pharmaceutical University, Nanjing, China.
Xuegan
X
Yang
Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center, Houston, USA.
Xiaodong
X
Cheng
School of Life Science &Technology, China Pharmaceutical University, Nanjing, China.
Yu
Y
Ou
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D056945:Hep G2 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010798:Phycocyanin / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
D009363:Neoplasm Proteins; D010798:Phycocyanin
Cancer Cell. 2006 Sep;10(3):215-26
16959613
Mol Pharmacol. 2007 Jul;72(1):29-39
17395690
Apoptosis. 2008 Jan;13(1):1-9
17990121
Mol Cancer Ther. 2003 Nov;2(11):1165-70
14617790
EMBO J. 2010 Feb 3;29(3):619-31
19959994
J Biomol Screen. 2009 Feb;14(2):142-50
19196697
Trends Cell Biol. 2011 Jul;21(7):387-92
21561772
IUBMB Life. 2006 Nov;58(11):621-31
17085381
Eur J Pharmacol. 2015 Feb 15;749:107-14
25617793
J Biol Chem. 2006 Dec 1;281(48):36883-90
17005556
Science. 1995 Nov 24;270(5240):1326-31
7481820
Oncogene. 2008 Dec;27 Suppl 1:S137-48
19641499
Oncogene. 2001 Jul 19;20(32):4365-72
11466617
Curr Protein Pept Sci. 2003 Jun;4(3):207-16
12769719
Blood. 2008 Apr 15;111(8):4365-74
18270325
J Biol Chem. 2000 Apr 28;275(17):12737-42
10777569
Biochem Pharmacol. 2004 Aug 1;68(3):453-62
15242812
Biomed Res Int. 2013;2013:742859
24063013
J Clin Invest. 2001 Jan;107(2):135-42
11160126
Aliment Pharmacol Ther. 2006 Jul 1;24(1):87-94
16803606
J Cell Sci. 2012 Nov 15;125(Pt 22):5259-68
23377657
Leukemia. 2013 Oct;27(10):2040-6
23538752
Cell Signal. 2014 Oct;26(10 ):2131-7
24971507
J Biol Chem. 2005 Sep 16;280(37):32081-9
16027121
Int J Mol Sci. 2013 Jan 16;14(1):1778-87
23325046
Oncogene. 2004 Apr 12;23(16):2891-906
15077152
Carcinogenesis. 2000 Jul;21(7):1423-32
10874022
Acta Biochim Biophys Sin (Shanghai). 2010 Jan;42(1):80-9
20043050
Cell Death Differ. 2015 Mar;22(3):367-76
25257169
Mediators Inflamm. 2008;2008:725854
18566685
Lancet. 2011 Aug 13;378(9791):607-20
21620466
Toxicol Lett. 2012 Apr 5;210(1):78-86
22322152
Clin Cancer Res. 2009 Sep 1;15(17):5308-16
19706824
Nature. 2003 Aug 14;424(6950):797-801
12917690
Cancer Lett. 2007 Mar 8;247(1):150-8
16740358
Oncogene. 2008 Oct 20;27(48):6245-51
18931691
Cell Death Differ. 2009 Jul;16(7):966-75
19325568
FEBS Lett. 2010 Apr 2;584(7):1287-95
20083114
Mol Cell Biol. 2009 May;29(10 ):2594-608
19289499
Am J Cancer Res. 2011;1(5):629-49
21994903
J Cell Sci. 2004 Oct 15;117(Pt 22):5197-208
15483317
Acta Biochim Biophys Sin (Shanghai). 2016 Jan;48(1):60-74
26637829
Gastroenterology. 2010 Aug;139(2):598-608
20434451
Science. 2004 Nov 5;306(5698):990-5
15528435
J Cell Biol. 2008 Oct 6;183(1):101-16
18838554
Nat Rev Mol Cell Biol. 2007 Sep;8(9):741-52
17717517
Int J Mol Sci. 2013 Nov 25;14 (12 ):23212-30
24287900
J Neuroimmunol. 2010 Sep 14;226(1-2):66-72
20554329
PLoS One. 2015 Feb 27;10(2):e0118985
25723496