Hakan SOYLU, Kübra AKSU, İsmail ÜSTÜNEL, Kayihan KARACOR, Özge BEYAZÇİÇEK

Abirateron ve Docetaxel Tedavileri Metastatik Prostat Kanseri Hücrelerinde Phospho-PTEN Ekspresyonunu Arttırır

Amaç: Prostat kanseri erkeklerde kanser ile ilişkili ölümlerde ikinci sırada yer almaktadır. Kastrasyona dirençli metastatik prostat kanseri tedavilerinde dosetaksel ve abirateron asetat yaygın olarak kullanılmaktadır. Phospho-PTEN, onkojenik Akt hiperaktivasyonuna sebep olarak hücrelerde proliferasyon, migrasyon, angiyogenez ve hayatta kalmayı tetikler. Bu çalışmada prostat kanseri tedavisinde yaygın olarak kullanılan dosetaksel ve abirateron asetat ajanlarının onkogenic yolağı uyaran phospho-PTEN ekspresyonu üzerine etkisinin araştırılması amaçlanmışır. Gereç ve Yöntemler: In vitro olarak antijen reseptör (+) ve androjen reseptör (-) metastatik prostat kanseri hücre hatlarında dosetaksel ve abirateron acetat’ın phospho-PTEN expresyonu üzerine etkisi immünofloresan yöntemi ile araştırılmıştır. Bulgular: Antijen reseptör (+) ve androjen reseptör (-) metastatik prostat kanseri hücre hatlarının her ikisinde de bulgular birbiriyle uyumluydu. Kontrol ve abirateron asetat grupları arasında phospho-PTEN ekspresyonununda istatistiksel olarak anlamlı bir fark gözlenmedi. Dosetaksel ve abirateron asetat+dosetaksel gruplarında phospho-PTEN ekspresyonu kontrole göre istatistiksel olarak anlamlı şekilde arttı. Bu artış iki ajanın birlikte verildiği kombine grupta dosetaksel grubuna kıyasla istatistiksel olarak anlamlı şekilde daha fazlaydı. Sonuç: Dosetaksel ve kombine tedavi gruplarında belirgin şekilde phospho-PTEN artışı gözlendi. Phospho-PTEN’in artışı onkojenik Akt hiperaktivasyonuna neden olmaktadır. Bu bilgilere göre, dosetaksel ve kombine ilaç tedavileri hastalarda phospho-PTEN artışına sebep olarak hücrelerde onkojenik yolağı destekliyor olabilir. Hastalarda bu etkilerinin bertaraf edilebilmesi için PTEN’i defosforile edici ajanlar ya da defosforilasyonu sağlayan yolakların uyarılmasını sağlayacak ajanların verilmesi hastaların toplam hayatta kalma sürelerini artırabilir.

Anahtar Kelimeler:

Prostat, Kanser, Phospho-PTEN, Docetaxel, Abirateron

Abiraterone and Docetaxel Treatments Increase Phospho-PTEN Expression in Metastatic Prostate Cancer Cells

Aim: Prostate cancer is the second leading cause of death in cancer-related deaths in men. Docetaxel and abiraterone acetate are widely used in the treatment of castration-resistant metastatic prostate cancer. Phospho-PTEN triggers proliferation, migration, angiogenesis and survival in cells by causing oncogenic Akt hyperactivation. This study, it is aimed to investigate the effects of docetaxel and abiraterone acetate agents, which are widely used in the treatment of prostate cancer, on the expression of phospho-PTEN, which stimulates the oncogenic pathway. Material and Methods: The effects of docetaxel and abiraterone acetate on phospho-PTEN expression in androgen receptor (+) and androgen receptor (-) metastatic prostate cancer cell lines were investigated in vitro by immunofluorescence method. Results: Findings were compatible in both androgen receptor (+) and androgen receptor (-) metastatic prostate cancer cell lines. No statistically significant difference in phospho-PTEN expression was observed between the control and abiraterone acetate groups. Phospho-PTEN expression was increased statistically significant in docetaxel and abiraterone acetate+docetaxel groups compared to control. This increase was greater statistically significant in the combined group given the two agents compared to the docetaxel group. Conclusion: A significant increase in phospho-PTEN was observed in the docetaxel and combined treatment groups. The increase of Phospho-PTEN causes oncogenic Akt hyperactivation. According to this information, docetaxel and combined drug treatments may support the oncogenic pathway in cells by increasing phospho-PTEN in patients. To eliminate these effects in patients, the administration of agents that dephosphorylate PTEN or agents that will stimulate the pathways that provide dephosphorylation may increase the total survival of the patients.

Keywords:

Prostate, Cancer, Phospho-PTEN, Docetaxel, Abiraterone,

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Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021; 71(3): 209-49.
Marques RB, Dits NF, Erkens-Schulze S, van Weerden WM, Jenster G. Bypass mechanisms of the androgen receptor pathway in therapy-resistant prostate cancer cell models. PLoS One. 2010; 5(10): e13500.
Harris WP, Mostaghel EA, Nelson PS, Montgomery B. Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion. Nat Clin Pract Urol. 2009; 6(2): 76-85.
Attard G, Sarker D, Reid A, Molife R, Parker C, de Bono JS. Improving the outcome of patients with castration-resistant prostate cancer through rational drug development. Br J Cancer. 2006; 95(7): 767-74.
Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate. CA Cancer J Clin. 1972; 22(4): 232-40.
Jenster G. The role of the androgen receptor in the development and progression of prostate cancer. Semin Oncol. 1999; 26(4): 407-21.
Attar RM, Takimoto CH, Gottardis MM. Castration-resistant prostate cancer: locking up the molecular escape routes. Clin Cancer Res. 2009; 15(10): 3251-5.
Petrylak DP, Tangen CM, Hussain MH, Lara PN, Jr., Jones JA, Taplin ME, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004; 351(15): 1513-20.
Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004; 351(15): 1502-12.
Pienta KJ. Preclinical mechanisms of action of docetaxel and docetaxel combinations in prostate cancer. Semin Oncol. 2001; 28(4 Suppl 15): 3-7.
Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011; 364(21): 1995-2005.
Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013; 368(2): 138-48.
Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008; 8(11): 4447-54.
Molina A, Belldegrun A. Novel therapeutic strategies for castration resistant prostate cancer: inhibition of persistent androgen production and androgen receptor mediated signaling. J Urol. 2011; 185(3): 787-94.
Potter GA, Barrie SE, Jarman M, Rowlands MG. Novel steroidal inhibitors of human cytochrome P45017 alpha (17 alpha-hydroxylase-C17,20-lyase): potential agents for the treatment of prostatic cancer. J Med Chem. 1995; 38(13): 2463-71.
Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1998; 273(22): 13375-8.
Ramaswamy S, Nakamura N, Vazquez F, Batt DB, Perera S, Roberts TM, et al. Regulation of G1 progression by the PTEN tumor suppressor protein is linked to inhibition of the phosphatidylinositol 3-kinase/Akt pathway. Proc Natl Acad Sci U S A. 1999; 96(5): 2110-5.
Chow JT, Salmena L. Recent advances in PTEN signalling axes in cancer. Fac Rev. 2020; 9: 31.
Alvarez-Garcia V, Tawil Y, Wise HM, Leslie NR. Mechanisms of PTEN loss in cancer: It's all about diversity. Semin Cancer Biol. 2019; 59: 66-79.
Vazquez F, Grossman SR, Takahashi Y, Rokas MV, Nakamura N, Sellers WR. Phosphorylation of the PTEN tail acts as an inhibitory switch by preventing its recruitment into a protein complex. J Biol Chem. 2001; 276(52): 48627-30.
Vazquez F, Ramaswamy S, Nakamura N, Sellers WR. Phosphorylation of the PTEN tail regulates protein stability and function. Mol Cell Biol. 2000; 20(14): 5010-8.
Chang CJ, Mulholland DJ, Valamehr B, Mosessian S, Sellers WR, Wu H. PTEN nuclear localization is regulated by oxidative stress and mediates p53-dependent tumor suppression. Mol Cell Biol. 2008; 28(10): 3281-9.
Barata JT. The impact of PTEN regulation by CK2 on PI3K-dependent signaling and leukemia cell survival. Adv Enzyme Regul. 2011; 51(1): 37-49.
Yang Z, Xie C, Xu W, Liu G, Cao X, Li W, et al. Phosphorylation and inactivation of PTEN at residues Ser380/Thr382/383 induced by Helicobacter pylori promotes gastric epithelial cell survival through PI3K/Akt pathway. Oncotarget. 2015; 6(31): 31916-26.
Cheong JW, Eom JI, Maeng HY, Lee ST, Hahn JS, Ko YW, et al. Phosphatase and tensin homologue phosphorylation in the C-terminal regulatory domain is frequently observed in acute myeloid leukaemia and associated with poor clinical outcome. Br J Haematol. 2003; 122(3): 454-6.
Kovacs KA, Lengyel F, Vertes Z, Kornyei JL, Gocze PM, Sumegi B, et al. Phosphorylation of PTEN (phosphatase and tensin homologue deleted on chromosome ten) protein is enhanced in human fibromyomatous uteri. J Steroid Biochem Mol Biol. 2007; 103(2): 196-9.
Nakahata S, Ichikawa T, Maneesaay P, Saito Y, Nagai K, Tamura T, et al. Loss of NDRG2 expression activates PI3K-AKT signalling via PTEN phosphorylation in ATLL and other cancers. Nat Commun. 2014; 5: 3393.
Bertacchini J, Mediani L, Beretti F, Guida M, Ghalali A, Brugnoli F, et al. Clusterin enhances AKT2-mediated motility of normal and cancer prostate cells through a PTEN and PHLPP1 circuit. J Cell Physiol. 2019; 234(7): 11188-99.
Soylu H, Kirca M, Avci S, Ozpolat B, Ustunel I. Antiandrogen abiraterone and docetaxel treatments affect Notch1, Jagged1 and Hes1 expressions in metastatic prostate cancer cells. Exp Mol Pathol. 2021; 119: 104607.
Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022; 72(1): 7-33.
Teo MY, Rathkopf DE, Kantoff P. Treatment of Advanced Prostate Cancer. Annu Rev Med. 2019; 70: 479-99.
Bertrand FE, McCubrey JA, Angus CW, Nutter JM, Sigounas G. NOTCH and PTEN in prostate cancer. Adv Biol Regul. 2014; 56: 51-65.