THE ROLE OF AUTOPHAGY IN ORAL CANCER

Abstract

Autophagy is a universally preserved process in which cells break down their own intracellular organelles to control their regular renewal and eliminate dysfunctional organelles to maintain a balance inside the cell. Autophagy is a biological mechanism that helps cells adapt and protect themselves against stressors such as hypoxia, nutrient deficiency, and energy deprivation. Disruption of autophagy has been linked to a range of diseases, such as neurological disorders, infectious diseases, and cancer. Oral cancer is a highly destructive illness that results in the loss of numerous lives globally annually. The existing array of therapy modalities fails to adequately address the requirements of patients. Personalized medicine or targeted medicines are necessary due to the heterogeneity of the disease. Hence, it is imperative to promptly identify possible targets for oral cancer therapy. Autophagy has been discovered to potentially play a function in both the inhibition and advancement of oral cancer. Cancer cells employ the autophagy mechanism to enhance their survival in response to the stress induced by chemotherapy. Hence, it is of utmost importance to comprehend the processes underlying the suppression of cytoprotective catabolism and the exploitation of autophagic cell death to enhance the susceptibility of malignant tumor cells to certain therapeutic drugs and devise efficacious treatment strategies.

Keywords

• ATG
• Cell
• Macroautophagy
• Microautophagy
• Squamous cell carcinoma

OTOFAJİNİN ORAL KANSERDEKİ ROLÜ

Abstract

Otofaji, hücrelerin düzenli yenilenmelerini kontrol etmek için hücre içi organellerini parçaladıkları ve hücre içindeki dengeyi korumak için işlevsiz organelleri ortadan kaldırdıkları evrensel olarak korunmuş bir süreçtir. Otofaji, hücrelerin hipoksi, besin eksikliği ve enerji yoksunluğu gibi stres faktörlerine karşı uyum sağlamalarına ve kendilerini korumalarına yardımcı olan biyolojik bir mekanizmadır. Otofajinin bozulması nörolojik bozukluklar, bulaşıcı hastalıklar ve kanser gibi bir dizi hastalıkla ilişkilendirilmiştir. Oral kanser, dünya genelinde her yıl çok sayıda kişinin hayatını kaybetmesine neden olan son derece yıkıcı bir hastalıktır. Mevcut tedavi yöntemleri, hastaların gereksinimlerini yeterince karşılayamamaktadır. Hastalığın heterojenliği nedeniyle kişiselleştirilmiş tıp veya hedefe yönelik ilaçlar gereklidir. Bu nedenle, oral kanser tedavisi için olası hedeflerin derhal belirlenmesi gerekmektedir. Otofajinin, oral kanserin hem inhibisyonunda hem de ilerlemesinde potansiyel olarak bir işlev oynadığı keşfedilmiştir. Kanser hücreleri, kemoterapinin neden olduğu strese yanıt olarak hayatta kalmalarını artırmak için otofaji mekanizmasını kullanır. Bu nedenle, malign tümör hücrelerinin belirli terapötik ilaçlara duyarlılığını artırmak ve etkili tedavi stratejileri geliştirmek için sitoprotektif katabolizmanın baskılanmasının ve otofajik hücre ölümünün kullanılmasının altında yatan süreçleri anlamak büyük önem taşımaktadır.

Keywords

• ATG
• Hücre
• Makrootofaji
• Mikrootofaji
• Skuamöz hücreli karsinom

References

1. References: 1. Behrends C, Sowa ME, Gygi SP, Harper JW. Network organization of the human autophagy system. Nat 2010;466(7302):68-76.
2. 2. Alexandra T, Marina IM, Daniela M, Ioana SI, Maria B, Radu R, et al. Autophagy—A Hidden but Important Actor on Oral Cancer Scene. Int J Mol Sci 2020;21(23):9325.
3. 3. Tekirdag K, Cuervo AM. Chaperone-mediated autophagy and endosomal microautophagy: Jointed by a chaperone. J Biol Chem 2018;293(15):5414-24.
4. 4. Debnath J, Gammoh N, Ryan KM. Autophagy and autophagy-related pathways in cancer. Nat Rev Mol Cell Biol 2023;24(8):560-575.
5. 5. Kumar M, Nanavati R, Modi TG, Dobariya C. Oral cancer: Etiology and risk factors: A review. J Cancer Res Ther 2016;12(2):458-63.
6. 6. Montero PH, Patel SG. Cancer of the oral cavity. Surg Oncol Clin 2015;24(3):491-508.
7. 7. Hayashi K, Suzuki Y, Fujimoto C, Kanzaki S. Molecular mechanisms and biological functions of autophagy for genetics of hearing impairment. Genes 2020;11(11):1331.
8. 8. Tang JY, Hsi E, Huang YC, Hsu NCH, Yang WC, Chang HW, et al. Overexpression of autophagy-related 16-like 1 in patients with oral squamous cell carcinoma. Pathol Oncol Res 2015;21:301-5.

9. 9. Liu J, Chen F, Lung J, Lo C, Lee F, Lu Y, et al. Prognostic significance of p62/SQSTM1 subcellular localization and LC3B in oral squamous cell carcinoma. Br J Cancer 2014;111(5):944-54.
10. 10. He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 2009;43:67-93.
11. 11. Tan Y-Q, Zhang J, Zhou G. Autophagy and its implication in human oral diseases. Autophagy 2017;13(2):225-36.
12. 12. Xie Y, Kang R, Sun X, Zhong M, Huang J, Klionsky DJ, et al. Posttranslational modification of autophagy-related proteins in macroautophagy. Autophagy 2015;11(1):28-45. 13. Kim YC, Guan KL. mTOR: a pharmacologic target for autophagy regulation. J Clin Investig 2015;125(1):25-32.
13. 14. Mizushima N, Yoshimori T, Ohsumi Y. The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol 2011;27:107-32.
14. 15. Parzych KR, Klionsky DJ. An overview of autophagy: morphology, mechanism, and regulation. Antioxid Redox Signal 2014;20(3):460-473.
15. 16. Zhang S, Yazaki E, Sakamoto H, Yamamoto H, Mizushima N. Evolutionary diversification of the autophagy-related ubiquitin-like conjugation systems. Autophagy 2022;18(12):2969-2984.
16. 17. Tanida I. Autophagosome formation and molecular mechanism of autophagy. Antioxid Redox Signal 2011;14(11):2201-14.
17. 18. D’souza S, Addepalli V. Preventive measures in oral cancer: An overview. Biomed Pharmacother 2018;107:72-80.
18. 19. Oji C, Chukwuneke F. Poor oral hygiene may be the sole cause of oral cancer. J Oral Maxillofac Surg 2012;11:379-83.
19. 20. Bais M. Impact of epigenetic regulation on head and neck squamous cell carcinoma. J Dent Res 2019;98(3):268-76.
20. 21. Chatzistefanou I, Lubek J, Markou K, Ord RA. The role of neck dissection and postoperative adjuvant radiotherapy in cN0 patients with PNI-positive squamous cell carcinoma of the oral cavity. Oral Oncol 2014;50(8):753-8.
21. 22. Ávalos Y, Canales J, Bravo-Sagua R, Criollo A, Lavandero S, Quest AF. Tumor suppression and promotion by autophagy. Biomed Res Int 2014;2014.
22. 23. De Lima T, Paz A, Rados P, Leonardi R, Bufo P, Pedicillo M, et al. Autophagy analysis in oral carcinogenesis. Pathol Res Pract 2017;213(9):1072-7.
23. 24. Terabe T, Uchida F, Nagai H, Omori S, Ishibashi-Kanno N, Hasegawa S, et al. Expression of autophagy-related markers at the surgical margin of oral squamous cell carcinoma correlates with poor prognosis and tumor recurrence. Hum Pathol 2018;73:156-63.
24. 25. Tang J-Y, Hsi E, Huang Y-C, Hsu NC-H, Chen Y-K, Chu P-Y, et al. ATG9A overexpression is associated with disease recurrence and poor survival in patients with oral squamous cell carcinoma. Virchows Arc 2013;463:737-42.
25. 26. Nomura H, Uzawa K, Yamano Y, Fushimi K, Ishigami T, Kouzu Y, et al. Overexpression and altered subcellular localization of autophagy-related 16-like 1 in human oral squamous-cell carcinoma: correlation with lymphovascular invasion and lymph-node metastasis. Hum Pathol 2009;40(1):83-91.
26. 27. Tang J-Y, Fang Y-Y, Hsi E, Huang Y-C, Hsu NC-H, Yang W-C, et al. Immunopositivity of Beclin-1 and ATG5 as indicators of survival and disease recurrence in oral squamous cell carcinoma. Anticancer Res 2013;33(12):5611-6.
27. 28. Ishimura R, Tanaka K, Komatsu M. Dissection of the role of p62/Sqstm1 in activation of Nrf2 during xenophagy. FEBS Lett 2014;588(5):822-8.
28. 29. Inui T, Chano T, Takikita-Suzuki M, Nishikawa M, Yamamoto G, Okabe H. Association of p62/SQSTM1 excess and oral carcinogenesis. PloS one 2013;8(9):e74398.
29. 30. Wang Y, Wang C, Tang H, Wang M, Weng J, Liu X, et al. Decrease of autophagy activity promotes malignant progression of tongue squamous cell carcinoma. J Oral Pathol Med 2013;42(7):557-64.
30. 31. Weng J, Wang C, Wang Y, Tang H, Liang J, Liu X, et al. Beclin1 inhibits proliferation, migration and invasion in tongue squamous cell carcinoma cell lines. Oral Oncol 2014;50(10):983-90.
31. 32. Mattoscio D, Medda A, Chiocca S. Human papilloma virus and autophagy. Int J Mol Sci 2018;19(6):1775.
32. 33. Lee YS, Eckers JC, Kimple RJ. Autophagy in head and neck cancer therapy. In: Kimple RJ, editor. Improving the Therapeutic Ratio in Head and Neck Cancer. 1st ed. Elsevier; 2020. p. 281-300. 34. Yang Z, Yan G, Zheng L, Gu W, Liu F, Chen W, et al. YKT6, as a potential predictor of prognosis and immunotherapy response for oral squamous cell carcinoma, is related to cell invasion, metastasis, and CD8+ T cell infiltration. Oncoimmunology 2021;10(1):1938890. 35. Tan YS, Sansanaphongpricha K, Xie Y, Donnelly CR, Luo X, Heath BR, et al. Mitigating SOX2-potentiated immune escape of head and neck squamous cell carcinoma with a STING-inducing nanosatellite vaccine. Clin Cancer Res 2018;24(17):4242-55.
33. 36. Yang Y, Ji C, Bi Z, Lu C, Wang R, Gu B, et al. Deguelin induces both apoptosis and autophagy in cultured head and neck squamous cell carcinoma cells. PloS one 2013;8(1):e54736.
34. 37. Xie J, Li Q, Ding X, Gao Y. Targeting mTOR by CZ415 inhibits head and neck squamous cell carcinoma cells. Cell Physiol Biochem 2018;46(2):676-86.
35. 38. Cai F, Xiao X, Niu X, Zhong Y. Association between promoter methylation of DAPK gene and HNSCC: A meta-analysis. PLoS One 2017;12(3):e0173194.
36. 39. Reis RSD, Santos JAD, Abreu PMD, Dettogni RS, Santos EDV, Stur E, et al. Hypermethylation status of DAPK, MGMT and RUNX3 in HPV negative oral and oropharyngeal squamous cell carcinoma. Genet Mol Biol 2020;43.
37. 40. Huang Z, Wang L, Wang Y, Zhuo Y, Li H, Chen J, et al. Overexpression of CD 147 contributes to the chemoresistance of head and neck squamous cell carcinoma cells. J Oral Pathol Med 2013;42(7):541-6. 41. Xu Z, Huang C-M, Shao Z, Zhao X-P, Wang M, Yan T-L, et al. Autophagy induced by areca nut extract contributes to decreasing cisplatin toxicity in oral squamous cell carcinoma cells: roles of reactive oxygen species/AMPK signaling. Int J Mol Sci 2017;18(3):524.
38. 42. Huang K, Liu D. Targeting non-canonical autophagy overcomes erlotinib resistance in tongue cancer. Tumor Biol 2016;37:9625-33.
39. 43. Cai Y, Tan X, Liu J, Shen Y, Wu D, Ren M, et al. Inhibition of PI3K/Akt/mTOR signaling pathway enhances the sensitivity of the SKOV3/DDP ovarian cancer cell line to cisplatin in vitro. Chin J Cancer Res 2014;26(5):564.