Inhibitory Effect of Bee Venom Toxin on the Growth of Cervix Cancer C33A Cells via Death Receptor Expression and Apoptosis

다국어 초록 (Multilingual Abstract)

Objectives : We investigated whether bee venom(BV) inhibit cell growth through enhancement of death receptor expressions in the human cervix cancer C33A cells.
Methods : BV(1~5 ㎍/㎖) inhibited the growth of cervix cancer C33A cells by the induction of apoptotic cell death in a dose dependent manner.
Results : Consistent with apoptotic cell death, expression of Fas, death receptor(DR) 3, 4, 5 and 6 was increased concentration dependently in the cells. Moreover, Fas, DR3 and DR6 revealed more sensitivity to BV. Thus, We reconfirmed whether they actually play a critical role in anti-proliferation of cervix cancer C33A cells. Consecutively, expression of DR downstream pro-apoptotic proteins including caspase-8, -3, -9 was upregulated and Bax was concomitantly overwhelmed the expression of Bcl-2. NF-κB were also inhibited by treatment with BV in C33A cells.
Conclusions : These results suggest that BV could exert anti-tumor effect through induction of apoptotic cell death in human cervix cancer C33A cells via enhancement of death receptor expression, and that BV could be a promising agent for preventing and treating cervix cancer.

참고문헌 (Reference)

1 Scaffidi C, "Two CD95(APO-1/Fas) signaling pathways" 17 (17): 1675-1687, 1998

2 Wallach D, "Tumor necrosis factor receptor and Fas signaling mechanisms" 17 (17): 331-337, 1999

3 Sheets EE, "The role of apoptosis in gynaecological malignancies" 29 (29): 121-126, 1997

4 Horinaka M, "The combination of TRAIL and luteolin enhances apoptosis in human cervical cancer HeLa cells" 333 (333): 833-838, 2005

5 Hengartner MO, "The biochemistry of apoptosis" 407 (407): 770-776, 2000

6 Peter ME, "The CD95(APO-1/Fas)DISC and beyond" 10 (10): 26-35, 2003

7 Ashkenazi A, "Targeting death and decoy receptors of the tumor necrosis factor superfamily" 2 (2): 420-430, 2002

8 Ghobrial IM, "Targeting apoptosis pathways in cancer therapy" 55 (55): 178-194, 2005

9 Enari M, "Sequential activation of ICE-like and CPP32-like proteases during Fas-mediated apoptosis" 380 (380): 723-726, 1996

10 Hougardy BM, "Sensitivity to Fas-mediated apoptosis in high- risk HPVpositive human cervical cancer cells. Relationship with Fas, caspase-8, and Bid" 97 (97): 353-364, 2005

11 Pozo-Guisado E, "Resveratrol induced apoptosis in MCF-7human breast cancer cells involves a caspaseindependent mechanism with downregulation of Bcl-2 and NF-kappaB" 115 (115): 74-84, 2005

12 Tyagi A, "Resveratrol causes Cdc2-try15 phosphorylation via ATM/ATR-Chk1/2-Cdc25C pathway as a central mechanism for S phase arrest in human ovarian carcinoma Ovcar-3 cell" 26 (26): 1978-1987, 2005

13 Levi F, "Resveratrol and breast cancer risk" 14 (14): 139-142, 2005

14 Le Corre L, "Resveratrol and breast cancer chemoprevention. Molecular mechanisms" 49 (49): 462-471, 2005

15 Whitney CW, "Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stages IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes. A Gynecologic Oncology Group and Southwest Oncology Group study" 17 (17): 1339-1348, 1999

16 Morris M, "Pelvic radiation with concurrent chemotherapy versus pelvic and para-aortic radiation for high-risk cervical cancer. A Randomized Radiation Therapy Oncology Group clinical trial" 340 (340): 1137-1143, 1999

17 Karin M, "Nuclear factor-kappaB in cancer development and progression" 441 (441): 431-436, 2006

18 Nair A, "NF-kappaB is constitutively activated in high-grade squamous intraepithelial lesions and squamous cell carcinomas of the human uterine cervix" 22 (22): 50-58, 2003

19 Costantini P, "Mitochondrion as a novel target of anticancer chemotherapy" 92 (92): 1042-1053, 2000

20 Green DR, "Mitochondria and apoptosis" 281 (281): 1309-1312, 1998

21 Wang C, "Melittin, a major component of bee venom, sensitizes human hepatocellular carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)-induced apoptosis by activating CaMKII-TAK1-JNK/p38 and inhibiting IκBα kinase-NFκB" 284 (284): 3804-3813, 2009

22 Liu S, "Melittin prevents liver cancer cell metastasis through inhibition of the Rac1-dependent pathway" 47 (47): 1964-1973, 2008

23 Jung Hyun Park, "Melittin Suppresses PMA-Induced Tumor Cell Invasion by Inhibiting NF-κB and AP-1-Dependent MMP-9 Expression" 한국분자세포생물학회 29 (29): 209-215, 2010

24 Horinaka M, "Luteolin induces apoptosis via death receptor 5upregulation in human malignant tumor cells" 24 (24): 7180-7189, 2005

25 장동민, "Inhibitory Effects of Bee Venom on Growth of A549 Lung Cancer Cells via Induction of Death Receptors" 대한침구의학회 30 (30): 57-70, 2013

26 Baatout S, "Increased radiation sensitivity of an eosinophilic cell line following treatment with epigallocatechingallate, resveratrol and curcuma" 15 (15): 337-352, 2005

27 James MA, "Human papillomavirus type 16 E6 activates NF-κB, induces cIAP-2 expression, and protects against apoptosis in a PDZ binding motif-dependent manner" 80 (80): 5301-5307, 2006

28 Koh WRP, "Gynecologic cancer:controversies in management, Vol" Elsevier Churchill-Livingstone 175-186, 2004

29 Parkin DM, "Global cancer statistics, 2002" 55 (55): 74-108, 2005

30 Timmer T, "Fas receptormediated apoptosis. A clinical application" 196 (196): 125-134, 2002

31 Ryu HS, "Expression of TRAIL(TNF-related apoptosisinducing ligand) receptors in cervical cancer" 10 (10): 417-424, 2000

32 Parkin DM, "Estimates of the worldwide incidence of eighteen major cancers in 1985" 54 (54): 594-606, 1993

33 Shen Xin, "Effects of res on proliferation and apoptosis of human cervical carcinoma cell lines C33A, SiHa and HeLa" 24 (24): 148-154, 2009

34 Yu L, "Effect of resveratrol on cell cycle proteins in murine transplantable liver cancer" 9 (9): 2341-2343, 2003

35 Kischkel FC, "Cytotoxicity-dependent APO-1(Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor" 14 (14): 5579-5588, 1995

36 Rose PG, "Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer" 340 (340): 1144-1153, 1999

37 PetersⅢ WA, "Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk earlystage cancer of the cervix" 18 (18): 1606-1613, 2000

38 Hee-SugRyu, "Concurrent Chemoradiotherapy in Cervical Cancer (A New Paradigm in Cervical Cancer Treatment)" 연세대학교의과대학 43 (43): 749-753, 2002

39 Hougardy BM, "Clinical potential of inhibitors of survival pathways and activators of apoptotic pathways in treatment of cervical cancer: changing the apoptotic balance" 6 (6): 589-598, 2005

40 Li H, "Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis" 94 (94): 491-501, 1998

41 Keys HM, "Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage in cervical carcinoma" 340 (340): 1154-1161, 1999

42 Cain K, "Caspase activation involves the formation of the aposome, a large(approximately 700 kDa) caspaseactivating complex" 274 (274): 22686-22692, 1999

43 Isacson C, "Both cell proliferation and apoptosis increase with lesion grade in cervical neoplasia but do not correlate with human papillomavirus type" 56 (56): 669-674, 1996

44 Luo X, "Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors" 94 (94): 481-490, 1998

45 Li J, "Association of constitutive nuclear factor-kappaB activation with aggressive aspects and poor prognosis in cervical cancer" 19 (19): 1421-1426, 2009

46 Kutuk O, "Aspirin inhibits TNFalphaand IL-1-induced NF-kappaB activation and sensitizes HeLa cells to apoptosis" 25 : 229-237, 2004

47 Reed JC, "Apoptosis-regulating proteins as targets for drug discovery" 7 (7): 314-319, 2001

48 Park HJ, "Antiarthritic effect of bee venom: inhibition of inflammation mediator generation by suppression of NF-κB through interaction with the p50 subunit" 50 (50): 3504-3515, 2004

49 Park MH, "Anti-cancer effect of bee venom in prostate cancer cells through activation of caspase pathway via inactivation of NF-ΚB" 71 (71): 801-812, 2011

50 Li JY, "3-(4-(Benzo[d]thiazol-2-yl) -1-phenyl-1Hpyrazol-3-yl)phenyl acetate induced HepG2 cell apoptosis through a ROS-mediated pathway" 183 (183): 341-348, 2010