Berrin TUĞRUL, Erdal BALCAN, Beyhan GÜRCÜ

Otofaji ve Kanser

Programlanmış tip II hücre ölüm tipi olan otofaji kendi kendini yeme işlemidir. Açlık ve diğer stres durumlarında biyomoleküllerin yapı taşlarının bazal seviyelerini koruyan hücre içi bir geri dönüşüm sürecidir. Lizozom aracılı katabolik bir süreç olan otofaji hücresel homeostazın sürdürülmesinde önemli bir role sahiptir. Otofaji tiplerinden biri olan makrootofaji yolağı, iç ve dış sinyallerin uyarımı sonucunda hücre içi sindirilecek materyal (yanlış katlanmış ya da bozulmuş proteinler, hasarlı organeller, vb.) otofagozom içine alınarak, otofagozomun lizozomla birleşmesi sonucu lizozomal aktivite ile sindirilmesi sürecini içerir. Otofaji sinyal yolağı otofaji ile ilişkili genler (ATG’ler)’in ürünleri ile ilave proteinler ve otofaji ile ilişkili kinazlar tarafından düzenlenmektedir. Otofaji mekanizmasındaki bozukluklar kanserin de dahil olduğu çeşitli hastalıklarla ilişkilendirilmektedir. Tümör oluşumu sırasında otofajinin kanserin erken evresinde tümör baskılayıcı, ileri evrede ise tümörü teşvik edici ikili bir role sahip olduğu çeşitli çalışmalarla ortaya konmuştur. Otofajinin karmaşık yapısı ve kanserdeki bu ikili rolü sebebiyle mekanizmanın tam olarak aydınlatılması ve farklı kanserlerde hangi aşamada nasıl bir role sahip olduğunun belirlenmesi ya otofaji baskılayıcı ya da otofajiyi teşvik edici etkin tedavilerin geliştirilmesine olanak tanıyacaktır. Bu derlemede, makrootofaji sinyal yolağının moleküler mekanizması, otofajinin kanserdeki ikili rolü ve otofaji ile ilişkili kansere karşı geliştirilen tedavi yaklaşımları hakkında bilgiler verilmesi amaçlanmıştır.

Anahtar Kelimeler:

otofaji, makrootofaji, kanser

Autophagy and Cancer

Autophagy, type II programmed cell death, is a self-eating process. It is an intracellular recycling process that maintains basal levels of the building blocks of biomolecules during starvation and other stress situations. Autophagy, a lysosome-mediated catabolic process, has an important role in maintaining cellular homeostasis. The macroautophagy pathway, which is one of the autophagy types, includes the process of ingestion of the intracellular digestible material (misfolded or disrupted proteins, damaged organelles, etc.) into the autophagosome, followed by the fusion of the autophagosome with the lysosome, and the process of digestion with lysosomal activity by the stimulation of internal and external signals. The autophagy signaling pathway is regulated by products of autophagy-related genes (ATGs), additional proteins, and autophagy-related kinases. Disturbances in the autophagy mechanism are associated with various diseases, including cancer. Various studies have demonstrated that autophagy has a dual role as tumor suppressor in the early stage of cancer and tumor promoting in the advanced stage during tumor formation. Due to the complex structure of autophagy and its dual role in cancer, the full elucidation of the mechanism and the determination of what role it plays in different cancers will allow the development of effective treatments that either suppress autophagy or promote autophagy. In this review, it is aimed to give information about the molecular mechanism of the macroautophagy signaling pathway, the dual role of autophagy in cancer and the treatment approaches developed against autophagy-related cancer.

Keywords:

autophagy, macroautophagy, cancer,

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Tang, D, Kang, R, Berghe, T.V, Vandenabeele, P, Kroemer, G, The molecular machinery of regulated cell death, Cell Research, 2019, 29(5), 347-364.
Zhao, Y.G, Zhang, H, Core autophagy genes and human diseases, Current Opinion Cell Biology, 2019, 61, 117-125.
Rubinsztein, D.C, Frake, R.A, Yoshinori Ohsumi's Nobel Prize for mechanisms of autophagy: from basic yeast biology to therapeutic potential, The Journal of the Royal College of Physicians of Edinburgh, 2016, 46(4), 228-233.
Mizushima, N, Komatsu, M, Autophagy: renovation of cells and tissues, Cell, 2011, 147(4), 728-741.
Lemasters, J.J, Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging, Rejuvenation Research, 2005, 8(1), 3-5.
Wang, C.W, Kim, J, Huang, W.P, Abeliovich, H, Stromhaug, P.E, Dunn, W.A, Jr, Klionsky, D. J, Apg2 is a novel protein required for the cytoplasm to vacuole targeting, autophagy, and pexophagy pathways, The Journal of Biological Chemistry, 2001, 276(32), 30442-30451.
Hung, Y.H, Chen, L.M, Yang, J.Y, Yang, W.Y, Spatiotemporally controlled induction of autophagy-mediated lysosome turnover, Nature Communications, 2013, 4, 2111.
Khaminets, A, Heinrich, T, Mari, M, Grumati, P, Huebner, A.K, Akutsu, M, Liebmann, L, Stolz, A, Nietzsche, S, Koch, N, Mauthe, M, Katona, I, Qualmann, B, Weis, J, Reggiori, F, Kurth, I, Hubner, C.A, Dikic, I, Regulation of endoplasmic reticulum turnover by selective autophagy, Nature, 2015, 522(7556), 354-358.
An, H, Harper, J.W, Systematic analysis of ribophagy in human cells reveals bystander flux during selective autophagy, Nature Cell Biology, 2018, 20(2), 135-143.
Oral, O, Akkoc, Y, Bayraktar, O, Gozuacik, D, Physiological and pathological significance of the molecular cross-talk between autophagy and apoptosis, Histology and Histopathology, 2016, 31(5), 479-498.
Wileman, T, Autophagy as a defence against intracellular pathogens, Essays in Biochemistry, 2013, 55, 153-163.
Huang, H, Kawamata, T, Horie, T, Tsugawa, H, Nakayama, Y, Ohsumi, Y, Fukusaki, E, Bulk RNA degradation by nitrogen starvation-induced autophagy in yeast, The EMBO Journal, 2015, 34(2), 154-168.
Saha, S, Panigrahi, D.P, Patil, S, Bhutia, S.K, Autophagy in health and disease: A comprehensive review, Biomedicine & Pharmacotheraphy, 2018, 104, 485-495.
Alberts, B, Heald, R, Morgan, D, Raff, M, Roberts, K, Walter, P, The Degradation and Recycling of Macromolecules in Lysosomes In: Molecular Biology of the Cell; 7th ed, W. W. Norton & Company, New York, USA, 2022, pp 798-810.
Kocaturk, N.M, Akkoc, Y, Kig, C, Bayraktar, O, Gozuacik, D, Kutlu, O, Autophagy as a molecular target for cancer treatment, European Journal of Pharmaceutical Sciences, 2019, 134, 116-137.
Komatsu, M, Waguri, S, Ueno, T, Iwata, J, Murata, S, Tanida I, Ezaki, J, Mizushima, N, Ohsumi, Y, Uchiyama, Y, Kominami, E, Tanaka, K, Chiba, T, Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice, The Journal of Cell Biology, 2005, 169(3), 425-434.
Karsli-Uzunbas, G, Guo, J.Y, Price, S, Teng, X, Laddha, S.V, Khor, S, Kalaany, N. Y, Jacks, T, Chan, C.S, Rabinowitz, J.D, White, E, Autophagy is required for glucose homeostasis and lung tumor maintenance, Cancer Discovery, 2014, 4(8), 914-927.
Fritzen AM, Madsen AB, Kleinert M, Treebak JT, Lundsgaard AM, Jensen TE, Richter, E.A, Wojtaszewski, J, Kiens, B, Frosig, C, Regulation of autophagy in human skeletal muscle: effects of exercise, exercise training and insulin stimulation, The Journal of Physiology, 2016, 594(3), 745-61.
Amaravadi, R.K, Kimmelman, A.C, Debnath, J, Targeting Autophagy in Cancer: Recent Advances and Future Directions, Cancer Discovery, 2019, 9(9), 1167-1181.
Kumar S, Gu Y, Abudu YP, Bruun JA, Jain A, Farzam F, Mudd, M, Anonsen, J.H, Rusten, T.E, Kasof, G, Ktistakis, N, Lidke, K.A, Johansen, T, Deretic, V, Phosphorylation of Syntaxin 17 by TBK1 Controls Autophagy Initiation, Developmental Cell, 2019, 49(1), 130-144 e6.
Chen, Y, Klionsky, D.J, The regulation of autophagy-unanswered questions, Journal of Cell Science, 2011, 124(Pt 2), 161-170.
Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, Packer, M, Schneider, M.D, Levine, B, Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy, Cell, 2005, 122(6), 927-939.
Liang, X.H, Jackson, S, Seaman, M, Brown, K, Kempkes, B, Hibshoosh, H, Levine, B, Induction of autophagy and inhibition of tumorigenesis by beclin 1, Nature, 1999, 402(6762), 672-6.
Fimia GM, Stoykova A, Romagnoli A, Giunta L, Di Bartolomeo S, Nardacci R, Corazzari, M, Fuoco, C, Ucar, A, Schwartz, P, Gruss, P, Piacentini, M, Chowdhury, K, Cecconi, F, Ambra1 regulates autophagy and development of the nervous system, Nature, 2007, 447(7148), 1121-1125.
Dooley, H.C, Razi, M, Polson, H.E, Girardin, S.E, Wilson, M.I, Tooze, S.A, WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5-16L1, Molecular Cell, 2014, 55(2), 238-252.
Rakesh, R, PriyaDharshini, L.C, Sakthivel, K.M, Rasmi, R.R, Role and regulation of autophagy in cancer, Biochimica et Biophysica Acta - Molecular Basis of Disease, 2022, 1868(7), 166400.
Guan, J.L, Simon, A.K, Prescott, M, Menendez, J.A, Liu, F, Wang, F, Wang, C, Wolvetang, E, Vazquez-Martin, A, Zhang, J, Autophagy in stem cells, Autophagy, 2013, 9(6), 830-849.
Aita, V.M, Liang, X.H, Murty, V.V, Pincus, D.L, Yu, W, Cayanis, E, Kalachikov, S, Gilliam, T.C, Levine, B, Cloning and genomic organization of beclin 1, a candidate tumor suppressor gene on chromosome 17q21, Genomics, 1999, 59(1), 59-65.
Qu, X, Yu, J, Bhagat, G, Furuya, N, Hibshoosh, H, Troxel, A, Rosen, J, Eskelinen, E.L, Mizushima, N, Ohsumi, Y, Cattoretti, G, Levine, B, Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene, The Journal of Clinical Investigation, 2003, 112(12), 1809-1820.
Yue, Z, Jin, S, Yang, C, Levine, A.J, Heintz, N, Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor, Proceedings of the National Academy of Sciences of the USA, 2003, 100(25), 15077-15082.
Maheshwari, C, Vidoni, C, Titone, R, Castiglioni, A, Lora, C, Follo, C, Isidoro, C, Isolation, Characterization, and Autophagy Function of BECN1-Splicing Isoforms in Cancer Cells, Biomolecules, 2022, 12(8), 1069.
Fu, L.L, Cheng, Y, Liu, B, Beclin-1: autophagic regulator and therapeutic target in cancer, The internaitonal Lournal of Biochemistry and Cell Biology, 2013, 45(5), 921-924.
Takahashi Y, Coppola D, Matsushita N, Cualing HD, Sun M, Sato Y, Liang, C, Jung, J.U, Cheng, J.Q, Mule, J.J, Pledger, W.J, Wang, H.G, Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis, Nature Cell Biology, 2007, 9(10), 1142-1151.
Kung, C.P, Budina, A, Balaburski, G, Bergenstock, M.K, Murphy, M, Autophagy in tumor suppression and cancer therapy, Critical Reviews in Eukaryotic Gene Expression, 2011, 21(1), 71-100.
Kang, M.R, Kim, M.S, Oh, J.E, Kim, Y.R, Song, S.Y, Kim, S.S, Ahn, C.H, Yoo, N.J, Lee, S.H, Frameshift mutations of autophagy-related genes ATG2B, ATG5, ATG9B and ATG12 in gastric and colorectal cancers with microsatellite instability, The Journal of Pathology, 2009, 217(5), 702-706.
Capparelli, C, Guido, C, Whitaker-Menezes, D, Bonuccelli, G, Balliet, R, Pestell, T.G, Goldberg, A.F, Pestell, R.G, Howell, A, Sneddon, S, Birbe, R, Tsirigos, A, Martinez-Outschoorn, U, Sotgia, F, Lisanti, M.P, Autophagy and senescence in cancer-associated fibroblasts metabolically supports tumor growth and metastasis via glycolysis and ketone production, Cell Cycle, 2012, 11(12), 2285-2302.
Watson, A.S, Riffelmacher, T, Stranks, A, Williams, O, De Boer, J, Cain, K, MacFarlane, M, McGouran, J, Kessler, B, Khandwala, S, Chowdhury, O, Puleston, D, Phadwal, K, Mortensen, M, Ferguson, D, Soilleux, E, Woll, P, Jacobsen, S.E, Simon, A.K, Autophagy limits proliferation and glycolytic metabolism in acute myeloid leukemia, Cell Death Discovery, 2015, 1, 15008-.
Pankiv, S, Clausen, T.H, Lamark, T, Brech, A, Bruun, J.A, Outzen, H, Overvatn, A, Bjorkoy, G, Johansen, T, p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy, The Journal of Biological Chemistry, 2007, 282(33), 24131-24145.
Islam, M.A, Sooro, M.A, Zhang, P, Autophagic Regulation of p62 is Critical for Cancer Therapy, International Journal of Molecular Sciences, 2018, 19(5).
White, E, The role for autophagy in cancer, The Journal of Clinical Investigation, 2015, 125(1), 42-6.
White, E, DiPaola, R.S, The double-edged sword of autophagy modulation in cancer, Clinical Cancer Research, 2009, 15(17), 5308-5316.
Li, X, He, S, Ma, B, Autophagy and autophagy-related proteins in cancer, Molecular Cancer, 2020, 19(1), 12.
White, E, Autophagy and p53, Cold Spring Harbor Perspectives in Medicine, 2016, 6(4), a026120.
Rao, S, Tortola, L, Perlot, T, Wirnsberger, G, Novatchkova, M, Nitsch, R, Sykacek, P, Frank, L, Schramek, D, Komnenovic, V, Sigl, V, Aumayr, K, Schmauss, G, Fellner, N, Handschuh, S, Glosmann, M, Pasierbek, P, Schlederer, M, Resch, G.P, Ma, Y, Yang, H, Popper, H, Kenner, L, Kroemer, G, Penninger, J.M, A dual role for autophagy in a murine model of lung cancer, Nature Communications, 2014, 5, 3056.
Cuyas, E, Corominas-Faja, B, Joven, J, Menendez, J.A, Cell cycle regulation by the nutrient-sensing mammalian target of rapamycin (mTOR) pathway, Methods in Molecular Biology, 2014, 1170, 113-144.
Fujii, S, Mitsunaga, S, Yamazaki, M, Hasebe, T, Ishii, G, Kojima, M, Kinoshita, T, Ueno, T, Esumi, H, Ochiai, A, Autophagy is activated in pancreatic cancer cells and correlates with poor patient outcome, Cancer Science, 2008, 99(9), 1813-1819.
Guo, J. Y., Karsli-Uzunbas, G., Mathew, R., Aisner, S. C., Kamphorst, J. J., Strohecker, A. M., Chen, G., Price, S., Lu, W., Teng, X., Snyder, E., Santanam, U., Dipaola, R. S., Jacks, T., Rabinowitz, J. D., White, E. Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis. Genes & Development, 2013, 27(13), 1447–1461.
Strohecker, A.M, Guo, J.Y, Karsli-Uzunbas, G, Price, S.M, Chen, G.J, Mathew, R, McMahon, M, White, E, Autophagy sustains mitochondrial glutamine metabolism and growth of BrafV600E-driven lung tumors, Cancer Discovery, 2013, 3(11), 1272-1285.
Foth, M, McMahon, M, Autophagy Inhibition in BRAF-Driven Cancers, Cancers (Basel), 2021, 13(14).
Wei, H, Wei, S, Gan, B, Peng, X, Zou, W, Guan, J.L, Suppression of autophagy by FIP200 deletion inhibits mammary tumorigenesis, Genes & Development, 2011, 25(14), 1510-1527.