Targeting cancer initiating cells by promoting cell differentiation and restoring chemosensitivity via dual inactivation of STAT3 and src activity using an active component of antrodia cinnamomea mycelia.
Cancer initiating cells (CICs) represent a subpopulation of cancer cells, which are responsible for tumor growth and resistance to chemotherapy. Herein, we first used a cell-based aldehyde dehydrogenase (ALDH) activity assay to identify that YMGKI-2 (also named as Ergone), an active component purified from Antrodia cinnamomea Mycelia extract (ACME), effectively abrogated the ALDH activity and abolished the CICs in head and neck squamous cell carcinoma cells (HNSCCs). Consequently, YMGKI-2 treatment suppressed self-renewal ability and expression of stemness signature genes (Oct-4 and Nanog) of sphere cells with enriched CICs. Moreover, YMGKI-2 treated sphere cells displayed reduction of CICs properties and promotion of cell differentiation, but not significant cytotoxicity. YMGKI-2 treatment also attenuated the tumorigenicity of HNSCC cells in vivo. Mechanistically, treatment of YMGKI-2 resulted in inactivation of STAT3 and Src. Lastly, combinatorial treatments with YMGKI-2 and standard chemotherapeutic drugs (cisplatin or Fluorouracil) restored the chemosensivity on sphere cells and cisplatin-resistant HNSCC cells. Together, we demonstrate that YMGKI-2 treatment effectively induces differentiation and reduces tumorigenicity of CICs. Further, combined treatment of YMGKI-2 and conventional chemotherapy can overcome chemoresistance. These results suggest that YMGKI-2 treatment may be used to improve future clinical responses in head and neck cancer treatment through targeting CICs.
Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.
Ching-Wen
CW
Chang
Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.
Yu-Syuan
YS
Chen
Department of Biotechnology, Hungkuang University, Taichung, Taiwan.
Chien-Chih
CC
Chen
Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.
Ik-On
IO
Chan
Grape King Inc., Taoyuan County, Taiwan.
Chin-Chu
CC
Chen
Grape King Inc., Taoyuan County, Taiwan.
Sen-Je
SJ
Sheu
Grape King Inc., Taoyuan County, Taiwan.
Ting-Wei
TW
Lin
Department of Life Science, Fu-Jen University, Taipei, Taiwan.
Shiu-Huey
SH
Chou
Department of Oral and Maxillofacial Surgery, Mackay Memorial Hospital, Taipei, Taiwan.
Chung-Ji
CJ
Liu
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Te-Chang
TC
Lee
Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.|Graduate Institute of Chinese Medical Science and Institute of Medical Science, China Medical University, Taichung, Taiwan.|Genome Research Center, National Yang-Ming University, Taipei, Taiwan.|Department of Dentistry, Taipei Veterans General Hospital, Taipei, Taiwan.
Jeng-Fan
JF
Lo
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001203:Ascomycota / Q000737:chemistry*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D000066673:Cell Self Renewal / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002783:Cholestenones / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D051379:Mice; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000970:Antineoplastic Agents; D002783:Cholestenones; D050796:STAT3 Transcription Factor; D019061:src-Family Kinases; D002945:Cisplatin; C015860:ergosta-4,6,8(14),22-tetraen-3-one
Differentiation; STAT3; cancer initiating cells; ergone; src
Evid Based Complement Alternat Med. 2011;2011:212641
19687189
J Nanosci Nanotechnol. 2013 Feb;13(2):1435-9
23646655
Oncotarget. 2015 Sep 22;6(28):25741-54
26325335
Exp Cell Res. 2012 Feb 15;318(4):336-49
22197704
Evid Based Complement Alternat Med. 2013;2013:946451
23843890
J Invest Dermatol. 1983 Jul;81(1 Suppl):100s-3s
6345687
N Engl J Med. 2008 Sep 11;359(11):1143-54
18784104
Cancer Causes Control. 2010 Sep;21(9):1427-35
20458529
Oncotarget. 2011 Jun;2(6):518-24
21680956
Cancer Res. 2006 Oct 1;66(19):9339-44
16990346
Evid Based Complement Alternat Med. 2012;2012:197309
23049605
Neoplasia. 2008 Feb;10(2):99-107
18283331
J Cell Physiol. 2010 Apr;223(1):14-26
20049846
Mol Oncol. 2014 Feb;8(1):142-9
24210755
Clin Cancer Res. 2013 Dec 1;19(23):6520-31
24141629
BMC Cancer. 2012 Jan 20;12:28
22260501
Oncotarget. 2016 Aug 16;7(33):53350-53361
27462789
Nat Med. 2011 Mar;17(3):313-9
21386835
Planta Med. 1997 Feb;63(1):86-8
17252333
Differentiation. 2001 Oct;68(4-5):270-9
11776479
Oncotarget. 2015 Jul 10;6(19):17832-46
26098777
Cancer Sci. 2012 Apr;103(4):684-90
22192169
Adv Enzyme Regul. 1984;22:27-55
6382953
Clin Chim Acta. 2012 Oct 9;413(19-20):1438-45
22687646
PLoS One. 2011;6(11):e28053
22140506
Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):973-8
17210912
Chem Pharm Bull (Tokyo). 2004 Aug;52(8):1005-8
15305003
Nat Prod Res. 2008;22(10):901-6
18626826
J Oral Pathol Med. 2011 Sep;40(8):621-8
21342274
J Ethnopharmacol. 2013 Aug 26;149(1):35-48
23811047
Mol Cancer Ther. 2010 Nov;9(11):2879-92
21062915
CA Cancer J Clin. 2012 Jan-Feb;62(1):10-29
22237781
Cell Cycle. 2011 May 1;10(9):1378-84
21552008
Oncotarget. 2015 Oct 27;6(33):34494-509
26460734
Clin Cancer Res. 2007 Jan 15;13(2 Pt 1):621-9
17255285
Oncotarget. 2015 Aug 28;6(25):21268-82
26020804
Clin Cancer Res. 2008 Jul 1;14 (13):4085-95
18593985
Oncogene. 2014 Mar 27;33(13):1670-9
23604114
Oncotarget. 2013 Dec;4(12):2462-75
24318570
Oncotarget. 2013 Oct;4(10):1698-1711
24091605
Mol Nutr Food Res. 2012 Aug;56(8):1247-58
22692956
Oral Oncol. 2011 Feb;47(2):83-91
21167769
J Cancer Res Clin Oncol. 1996;122(4):243-8
8601578
Biochim Biophys Acta. 2011 Apr;1810(4):384-90
21241775
J Md State Dent Assoc. 1989 Spring;32(1):30-70
2689550
Gastroenterology. 2011 Jan;140(1):297-309
20951698
J Ethnopharmacol. 2009 Jan 21;121(2):194-212
19061947
Zhongguo Zhong Yao Za Zhi. 2014 Oct;39(20):3905-9
25751937
Nat Prod Res. 2011 Sep;25(16):1488-96
21337253
Cell Stem Cell. 2011 Jul 8;9(1):50-63
21726833
Oncotarget. 2015 Jul 30;6(21):18504-17
26098778
Mol Cancer. 2010 Oct 27;9:283
20979610
J Ethnopharmacol. 2009 Oct 29;126(1):184-7
19665537
J Pharm Pharmacol. 2011 Dec;63(12 ):1581-6
22060289
Cancer Res. 2014 Nov 1;74(21):6291-305
25217518