Preoperative Somatostatin Analogue Treatment Might Trigger Apoptosis and Autophagy in Tumor Tissues of Patients with Acromegaly: A Pilot Study

Abstract

Objective: To evaluate the effect of preoperative somatostatin analog (SRL) treatment on proteins associated with apoptosis and autophagy in patients with acromegaly and to determine factors correlating with these parameters.

Methods: Ex-vivo tumor samples of 11 SRL-treated and 9 SRL-untreated patients were retrospectively included in the study. Apoptotic and autophagic proteins were determined via immunohistochemical staining and apoptosis was evaluated via in situ DNA end labeling (TUNEL).

Results: TUNEL, caspase-3, and ATG-5 immunopositivity was significantly increased (p<0.01, p=0.01, p=0.01, respectively), survivin and beclin-1 immunopositivity was significantly decreased (p=0.03, p=0.02, respectively) in SRL-treated patients as compared with SRL-untreated controls. Ki-67 index was decreased significantly in the SRL-treated group (p=0.01). Significant positive correlations were detected between TUNEL and caspase-3 immunopositivity (r=0.577, p<0.01), and between survivin and beclin-1 immunopositivity (r=0.503, p=0.03). Age at diagnosis, preoperative GH, IGF-1 levels, tumor size, and invasion status were not found to affect TUNEL positivity nor did they correlate with caspase-3, survivin, beclin-1, ATG-5 immunopositivity (p>0.05 for all). Preoperative SRL treatment was the only factor that had a significant effect on TUNEL positivity (adjusted R²=0.39, p=0.02). Preoperative treatment duration was positively correlated with TUNEL and caspase-3 immunopositivity (r=0.526, p=0.02; r=0.475, p=0.04, respectively) and negatively correlated with survivin immunopositivity (r=−0.533, p=0.01).

Conclusions: Somatostatin analog treatment might induce apoptosis, increase autophagy, and decrease cell proliferation in GH-secreting adenomas. Also, proteins related to cross-talk between autophagy and apoptosis are upregulated after SRL treatment.

Key words

acromegaly - apoptosis - autophagy - somatostatin

^* Fatma Kaya Dagistanli and Hande Mefkure Ozkaya equally contributed to this study.

• References

• 1 Melmed S. Acromegaly pathogenesis and treatment. J Clin Invest 2009; 119: 3189-3202 10.1172/jci39375
• 2 Losa M, Ciccarelli E, Mortini P. et al. Effects of octreotide treatment on the proliferation and apoptotic index of GH-secreting pituitary adenomas. J Clin Endocrinol Metab 2001; 86: 5194-5200 10.1210/jcem.86.11.7986
• 3 Cap J, Cerman J, Nemecek S. et al. The influence of treatment with somatostatin analogues on morphology, proliferative and apoptotic activity in GH-secreting pituitary adenomas. J Clin Neurosci 2003; 10: 444-448
• 4 Colao A, Auriemma RS, Lombardi G. et al. Resistance to somatostatin analogs in acromegaly. Endocr Rev 2011; 32: 247-271 10.1210/er.2010-0002
• 5 Ferrante E, Pellegrini C, Bondioni S. et al. Octreotide promotes apoptosis in human somatotroph tumor cells by activating somatostatin receptor type 2. Endocr Relat Cancer 2006; 13: 955-962 10.1677/erc.1.01191
• 6 Acunzo J, Thirion S, Roche C. et al. Somatostatin receptor sst2 decreases cell viability and hormonal hypersecretion and reverses octreotide resistance of human pituitary adenomas. Cancer Res 2008; 68: 10163-10170 10.1158/0008-5472.can-08-1857
• 7 Sharma K, Patel YC, Srikant CB. Subtype-selective induction of wild-type p53 and apoptosis, but not cell cycle arrest, by human somatostatin receptor 3. Mol Endocrinol 1996; 10: 1688-1696 10.1210/mend.10.12.8961277
• 8 Theodoropoulou M, Zhang J, Laupheimer S. et al. Octreotide, a somatostatin analogue, mediates its antiproliferative action in pituitary tumor cells by altering phosphatidylinositol 3-kinase signaling and inducing Zac1 expression. Cancer Res 2006; 66: 1576-1582 10.1158/0008-5472.can-05-1189
• 9 Kulig E, Jin L, Qian X. et al. Apoptosis in nontumorous and neoplastic human pituitaries: expression of the Bcl-2 family of proteins. Am J Pathol 1999; 154: 767-774 10.1016/s0002-9440(10)65323-0
• 10 Saitoh Y, Arita N, Ohnishi T. et al. Absence of apoptosis in somatotropinomas treated with octreotide. Acta Neurochir (Wien) 1997; 139: 851-856
• 11 Sambaziotis D, Kapranos N, Kontogeorgos G. Correlation of bcl-2 and bax with apoptosis in human pituitary adenomas. Pituitary 2003; 6: 127-133
• 12 Guzzo MF, Carvalho LR, Bronstein MD. Apoptosis: its role in pituitary development and neoplastic pituitary tissue. Pituitary 2014; 17: 157-162 10.1007/s11102-013-0481-5
• 13 Fukuda S, Pelus LM. Survivin a cancer target with an emerging role in normal adult tissues. Mol Cancer Ther 2006; 5: 1087-1098 10.1158/1535-7163.mct-05-0375
• 14 Jankowska A, Wasko R, Waligorska-Stachura J. et al. Survivin products in pituitary tumors. Neuro Endocrinol Lett 2008; 29: 1033-1037
• 15 Waligorska-Stachura J, Andrusiewicz M, Sawicka-Gutaj N. et al. Evaluation of survivin splice variants in pituitary tumors. Pituitary 2015; 18: 410-416 10.1007/s11102-014-0590-9
• 16 Hsieh YC, Athar M, Chaudry IH. When apoptosis meets autophagy: deciding cell fate after trauma and sepsis. Trends Mol Med 2009; 15: 129-138 10.1016/j.molmed.2009.01.002
• 17 Chen N, Karantza-Wadsworth V. Role and regulation of autophagy in cancer. Biochim Biophys Acta 2009; 1793: 1516-1523 10.1016/j.bbamcr.2008.12.013
• 18 Niu TK, Cheng Y, Ren X. et al. Interaction of Beclin 1 with survivin regulates sensitivity of human glioma cells to TRAIL-induced apoptosis. FEBS Lett 2010; 584: 3519-3524 10.1016/j.febslet.2010.07.018
• 19 Djavaheri-Mergny M, Maiuri MC, Kroemer G. Cross talk between apoptosis and autophagy by caspase-mediated cleavage of Beclin 1. Oncogene 2010; 29: 1717-1719 10.1038/onc.2009.519
• 20 Pyo JO, Jang MH, Kwon YK. et al. Essential roles of Atg5 and FADD in autophagic cell death: dissection of autophagic cell death into vacuole formation and cell death. J Biol Chem 2005; 280: 20722-20729 10.1074/jbc.M413934200
• 21 Choi KS. Autophagy and cancer. Exp Mol Med 2012; 44: 109-120 10.3858/emm.2012.44.2.033
• 22 Weckman A, Rotondo F, Di Ieva A. et al. Autophagy in endocrine tumors. Endocr Relat Cancer 2015; 22: R205-R218 10.1530/erc-15-0042
• 23 Hatipoglu E, Bozcan S, Kadioglu P. Discontinuation of somatostatin analogs while acromegaly is in long-term remission. Pituitary 2015; 18: 554-560 10.1007/s11102-014-0608-3
• 24 Katznelson L, Laws Jr ER, Melmed S. et al. Acromegaly: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2014; 99: 3933-3951 10.1210/jc.2014-2700
• 25 Kaya Dagistanli F, Susleyici Duman B, Ozturk M. Protective effects of a calcium channel blocker on apoptosis in thymus of neonatal STZ-diabetic rats. Acta Histochem 2005; 107: 207-214 10.1016/j.acthis.2005.03.005
• 26 Kaya-Dagistanli F, Tanriverdi G, Altinok A. et al. The effects of alpha lipoic acid on liver cells damages and apoptosis induced by polyunsaturated fatty acids. Food Chem Toxicol 2013; 53: 84-93 10.1016/j.fct.2012.11.026
• 27 Gruszka A, Kunert-Radek J, Pawlikowski M. The effect of octreotide and bromocriptine on expression of a pro-apoptotic Bax protein in rat prolactinoma. Folia Histochem Cytobiol 2004; 42: 35-39
• 28 Bevan JS. Clinical review: The antitumoral effects of somatostatin analog therapy in acromegaly. J Clin Endocrinol Metab 2005; 90: 1856-1863 10.1210/jc.2004-1093
• 29 Wasko R, Jankowska A, Kotwicka M. et al. Effects of treatment with somatostatin analogues on the occurrence of apoptosis in somatotropinomas. Neuro Endocrinol Lett 2003; 24: 334-338
• 30 Fimia GM, Piacentini M. Regulation of autophagy in mammals and its interplay with apoptosis. Cell Mol Life Sci 2010; 67: 1581-1588 10.1007/s00018-010-0284-z
• 31 Jain MV, Paczulla AM, Klonisch T. et al. Interconnections between apoptotic, autophagic and necrotic pathways: implications for cancer therapy development. J Cell Mol Med 2013; 17: 12-29 10.1111/jcmm.12001
• 32 Kang R, Zeh HJ, Lotze MT. et al. The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ 2011; 18: 571-580 10.1038/cdd.2010.191
• 33 Yousefi S, Perozzo R, Schmid I. et al. Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat Cell Biol 2006; 8: 1124-1132 10.1038/ncb1482
• 34 Rubinstein AD, Eisenstein M, Ber Y. et al. The autophagy protein Atg12 associates with antiapoptotic Bcl-2 family members to promote mitochondrial apoptosis. Mol Cell 2011; 44: 698-709 10.1016/j.molcel.2011.10.014
• 35 Wirawan E, Vande Walle L, Kersse K. et al. Caspase-mediated cleavage of Beclin-1 inactivates Beclin-1-induced autophagy and enhances apoptosis by promoting the release of proapoptotic factors from mitochondria. Cell Death Dis 2010; 1: e18 10.1038/cddis.2009.16