Survivin and Telomerase as Radiotherapeutic Response Predictors of Subjects with Stage IIIB Cervical Squamous Cell Carcinoma

Fitriyadi Kusuma, Andrijono Andrijono, Ani Retno Prijanti, Laila Nuranna, Sri Mutya Sekarutami, Bambang Sutrisna, Ferry Sandra


BACKGROUND: Cervical cancer is one of the most prevalent cancers in women. Even with similar clinicopathologic features, radiotherapy outcomes are still vary among patients. This research was conducted to measure radiotherapy responses on cervical cancer patients by using Survivin, Telomerase and Cytochrome C.

METHODS: Subjects who matched the criteria were selected and requested to fill questionnaires. Subjects were then evaluated with magnetic resonance imaging (MRI) pre- and post-3D conformal radiotherapy. Histopathological study was conducted using resected tumors to determine the differentiation type. Enzyme-linked Immunosorbent Assays for detection of Survivin, Telomerase and Cytochrome C was performed using the resected tumors as well.

RESULTS: There were 76 patients in this study. Mean ofage was 50 and diameter of tumor size was 5.35 cm. Mean levels of Survivin, Telomerase and Cytochrome C were 632.82 pg/mL, 5.59 pg/mL and 204.75 ng/mL, respectively. There were significant correlations between radiotherapy response and Survivin (p=0.041) or Telomerase (p=0.022). Subjects with lower Survivin level (<932 pg/mL) had higher 1-year survival rate (63%) than subjects with higher Survivin level (50%). Similar results were obtained for subjects with lower Telomerase level (<5.75 pg/mL), who had higher 1-year survival rate (60%) than subjects with higher Telomerase level (43%).

CONCLUSION: Since radiotherapy response is significantly correlated with Survivin and Telomerase levels and subjects with lower Survivin or Telomerase level have higher 1-year survival rate, it can be suggested that Survivin and Telomerase could be potential predictors of radiotherapeutic response for subjects with stage IIIB cervical squamous cell carcinoma.

KEYWORDS: cervical cancer, radiotherapy Survivin, Telomerase, Cytochrome C

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Lindel K, Burri P, Studer HU, Altermatt HJ, Greiner RH, Gruber G. Human papillomavirus status in advanced cervical cancer: predictive and prognostic significance for curative radiation treatment. Int J Gynecol Cancer. 2005; 15: 278-84, CrossRef.

Franco EL, Duarte-Franco E, Ferenczy A. Cervical cancer: epidemiology, prevention and the role of human papillomavirus infection. CMAJ. 2001; 164: 1017-25, PMID.

Castellsagué X. Natural history and epidemiology of HPV infection and cervical cancer. Gynecol Oncol. 2008; 110: S4-7, CrossRef.

Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer. 2006; 118: 3030-44, PMID.

Andrijono. Kanker serviks. 3th Ed. Jakarta: Pustaka Spirit; 2009.

Aziz MF. Masalah kanker serviks. Cermin Dunia Kedokteran. 2001; 133: 5-7.

Long HJ, Laack NN, Gostout BS. Prevention, diagnosis, and treatment of cervical cancer. Mayo Clin Proc. 2007; 82: 1566-74, CrossRef.

Rose PG. Chemoradiotherapy: the new standard care for invasive cervical cancer. Drugs. 2000; 60: 1239-44, CrossRef.

Friedlander M, Grogan M, U.S. Preventative Services Task Force. Guidelines for the treatment of recurrent and metastatic cervical cancer. Oncologist. 2002; 7: 342-7, CrossRef.

Perez CA, Grigsby PW, Camel HM, Galakatos AE, Mutch D, Lockett MA. Irradiation alone or combined with surgery in stage IB, IIA, and IIB carcinoma of uterine cervix: update of a nonrandomized comparison. Int J Radiat Oncol Biol Phys. 1995; 31: 703-16, CrossRef.

Gadducci A, Tana R, Fanucchi A, Genazzani AR. Biochemical prognostic factors and risk of relaps in patients with cervical cancer. Gynecol Oncol. 2007; 107: S23-6, CrossRef.

Zusterzeel PL, Span PN, Dijsterhuis MG, Thomas CM, Sweep FC, Massuger LF. Serum vasculer endothelial growth factor: a prognostic factor in cervical cancer. J Cancer Res Clin Oncol. 2009; 135: 283-90, CrossRef.

Li K, Li Y, Shelton JM, Richardson JA, Spencer E, Chen ZJ, et al. Cytochrome c deficiency causes embryonic lethality and attenuates stress-induced apoptosis. Cell. 2000; 101: 389-99, CrossRef.

Pan J, Xu G, Yeung SC. Cytochrome c release is upstream to activation of caspase-9, caspase-8, and caspase-3 in the enhanced apoptosis of anaplastic thyroid cancer cells induced by manumycin and paclitaxel. J Clin Endocrinol Metab. 2001; 86: 4731-40, CrossRef.

Lin HI, Lee YJ, Chen BF, Tsai MC, Lu JL, Chou CJ, et al. Involvement of Bcl-2 family, cytochrome c and caspase-3 in induction of apoptosis by beauvericin in human non-small cell lung cancer cells. Cancer Lett. 2005; 230: 248-59, CrossRef.

Sun Y, Tang XM, Half E, Kuo MT, Sinicrope FA. Cyclooxygenase-2 overexpression reduces apoptotic susceptibility by inhibiting the cytochrome c-dependent apoptotic pathway in human colon cancer cells. Cancer Res. 2002; 62: 6323-8, PMID.

Herman-Antosiewicz A, Johnson DE, Singh SV. Sulforaphane causes autophagy to inhibit release of cytochrome C and apoptosis in human prostate cancer cells. Cancer Res. 2006; 66: 5828-35, CrossRef.

Way TD, Kao MC, Lin JK. Degradation of HER2/neu by apigenin induces apoptosis through cytochrome c release and caspase-3 activation in HER2/neuoverexpressing breast cancer cells. FEBS Lett. 2005; 579: 145-52, CrossRef.

Arung ET, Wicaksono BD, Handoko YA, Kusuma IW, Shimizu K, Yulia D, et al. Cytotoxic effect of artocarpin on T47D cells. J Nat Med. 2010; 64: 423-9, CrossRef.

Sandra F. Targeting Ameloblatoma into Apoptosis. Indones Biomed J. 2018; 10: 35-9, CrossRef.

Wolf BB, Schuler M, Li W, Eggers-Sedlet B, Lee W, Tailor P, et al. Defective cytochrome c-dependent caspase activation in ovarian cancer cell lines due to diminished or absent apoptotic protease activating factor-1 activity. J Biol Chem. 2001; 276: 34244-51, CrossRef.

Suzuki S, Higuchi M, Proske RJ, Oridate N, Hong WK, Lotan R. Implication of mitochondria-derived reactive oxygen species, cytochrome C and caspase-3 in N-(4-hydroxyphenyl)retinamideinduced apoptosis in cervical carcinoma cells. Oncogene. 1999; 18: 6380-7, CrossRef.

Ferry S, Matsuda M, Yoshida H, Hirata M. Inositol hexakisphosphate blocks tumor cell growth by activating apoptotic machinery as well as by inhibiting the Akt/NFkappaB-mediated cell survival pathway. Carcinogenesis. 2002; 23: 2031-41, CrossRef.

Altieri DC. Survivin, versatile modulation of cell division and apoptosis in cancer. Oncogene. 2003; 22: 8581-9, CrossRef.

Sandra F, Khosravi-Far R. Ser81 Survivin Induced Protein Kinase A (PKA)-dependent Phosphatidylinositol 3-kinase (PI3K) Activity. Indones Biomed J. 2014; 6: 157-62, CrossRef.

O'Driscoll L, Linehan R, Clynes M. Survivin: role in normal cells and in pathological conditions. Curr Cancer Drug. 2003; 3: 131-52, CrossRef.

Chakravarti A, Zhai GG, Zhang M, Malhotra R, Latham DE, Delaney MA, et al. Survivin enhances radiation resistance in primary human glioblastoma cells via caspase-independent mechanisms. Oncogene. 2004; 23: 7494-506, CrossRef.

Kennedy SM, O'Driscoll L, Purcell R, Fitz-simons N, McDermott EW, Hill AD, et al. Prognostic importance of survivin in breast cancer. Br J Cancer. 2003; 88: 1077-83, CrossRef.

Rodel F, Hoffmann J, Distel L, Herrmann M, Noisternig T, Papadopoulos T, et al. Survivin as a radioresistance factor, and prognostic and therapeutic target for radiotherapy in rectal cancer. Cancer Res. 2005; 65: 4881-7, CrossRef.

Smith SD, Wheeler MA, Plescia J, Colberg JW, Weiss RM, Altieri DC. Urine detection of survivin and diagnosis of bladder cancer. JAMA. 2001; 285: 324-8, CrossRef.

Reddy VG, Khanna N, Jain SK, Das BC, Singh N. Telomerase-A molecular marker for cervical cancer screening. Int J Gynecol Cancer. 2001; 11: 100-6, CrossRef.

Philippi C, Loretz B, Schaefer UF, Lehr CM. Telomerase as an emerging target to fight cancer: opportunities and challenges for nanomedicine. J Control Release. 2010; 146: 228-40, CrossRef.

Zaffaroni N, Pennati M, Colella G, Perego P, Supino R, Gatti L, et al. Expression of the anti-apoptotic gene survivin correlates with taxol resistance in human ovarian cancer. Cell Mol Life Sci. 2002; 59: 1406-12, CrossRef.

Zhang R, Wang T, Li KN, Qin WW, Chen R, Wang K, et al. A surviving double point mutant has potent inhibitory effect on the growth of hepatocellular cancer cells. Cancer Biol Ther. 2008; 7: 547-54, CrossRef.

Sandra F, Khosravi-Far R. Survivin S81A Enhanced TRAIL's Activity in Inducing Apoptosis. Indones Biomed J. 2010; 2: 113-7, CrossRef.

Sandra F, Khosravi-Far R. Phosphorylated-Survivin at Ser81 Induced Protein Kinase A (PKA): A Back Loop. Indones Biomed J. 2011; 3: 138-42, CrossRef.

Sandra F. Survivin Ser81 Plays an Important Role in PI3K/Akt/mTOR Signaling Pathway. Mol Cell Biomed Sci. 2018; 2: 55-9, CrossRef.

González-Suárez E, Samper E, Flores JM, Blasco MA. Telomerase-deficient mice with short telomeres are resistant to skin tumorigenesis. Nat Genet. 2000; 26: 114-7, CrossRef.

Holysz H, Lipinska N, Paszel-Jaworska A, Rubis B. Telomerase as a useful target in cancer fighting the breast cancer case. Tumour Biol. 2013; 34: 1371-80, CrossRef.

Eleftheriadis T, Pissas G, Liakopoulos V, Stefanidis I. Cytochrome c as a potentially clinical useful marker of mitochondrial and cellular damage. Front Immunol. 2016; 7: 279, CrossRef.



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