Publication: PANC-1 ve PANC10.05 pankreas kanseri hücre hatlarında palbociclib ve abemaciclib uygulamasıyla PI3K/AKT/MTOR ve AMPK sinyal ekseninin incelenmesi
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Date
2020
Authors
Çoban, Merve Nur
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İstanbul Kültür Üniversitesi / Lisansüstü Eğitim Enstitüsü / Moleküler Biyoloji ve Genetik Ana Bilim Dalı / Moleküler Biyoloji ve Genetik Bilim Dalı
Abstract
Pankreas duktal adenokarsinoma (PDAC), pankreas tümörlerinin yaklaşık % 85'ini oluşturan ve en sık görülen pankreas kanseri türüdür. Günümüzde pankreas kanseri yüksek mortalite oranına sahip olan ve sağkalım oranı oldukça düşüktür. Genetik ve biyolojik olarak farklı mutasyonlar içermesi nedeniyle kanserin birçok alt tipi farklı agresiflik düzeyleri ile ilişkilendirilmektedir ve agresif doğası gereği, kanser mortalite istatistiklerinde dördüncü sırada yer almaktadır. Hücre içerisindeki sinyal mekanizmalarındaki bozulmalar devamlı proliferasyonla ve sağkalımla sonuçlanmaktadır. Pankreas kanseri gelişiminde rol oynayan KRAS genindeki mutasyon hücre sağkalımı ile ilişkili PI3K/AKT/mTOR sinyal yolu aktive etmektedir. Ayrıca hücre siklusundaki CDK2NA ve tümör supresör TP53 deki aktivasyon kaybı kontrolsüz hücre çoğalmasına neden olmaktadır. Hücre içerisinde enerji sensörü olarak mevcudiyetini koruyan ve hücre siklusu ile etkileşimde olan AMPK nın değişimi kanser agresivitesinin gelişmesinde önemli rol oynamaktadır. Hücre döngüsündeki ve ilişkide bulunduğu sinyal yollarındaki bu kararsızlık ve sürekli proliferasyon kanser tedavisinde CDK inhibitörlerinin terapötik olarak etkinliklerinin geliştirilmesine olanak sağlamaktadır. Meme kanseri tedavisinde kullanılan CDK4/6 inhibitörleri olan palbociclib ve abemaciclib tek başına veya combine tedavilerle tercih edilen önemli terapötik ajanlardır. Pek çok kanser tipinde de etkileri araştırılan bu küçük moleküllü inhibitörlerin birçok sinyal mekanizmasının regülasyonunda önemlidir. Bu çalışmada seçili pankreas kanseri hücre hatlarında CDK4/6 inhibitörleri palbociclib ve abemaciclib uygulaması sonucu potansiyel terapötik yetkinliklerinin AMPK'nında ilişkide olduğu alt ve üst sinyal yollarındaki protein ve lipid profilleri üzerine etkileri incelenmiştir. Metabolik yeniden programlamanın, kanser hücrelerini farklı ortamlara daha uyumlu hale getiren kanserlerin önemli bir özellik olarak karşımıza çıktığı ve bunu modüle eden AMPK nın bu süreçte karar mekanizmasında önemli bir role sahip olduğu sonucuna varılmıştır. Lipit sentezinin arttığı bilinen pankreas kanserinde lipit sentez sürecinin bastırılmasının kanser tedavisi için önemli bir hedef olabileceği düşünülmektedir. Hücrelerde enerji metabolizmasının yeniden programlanması yolu ile CDKi'lerin pankreas kanserinde AMPK alt ve üst yolakları ile ilişkili olarak bir terapötik hedef olabileceği ortaya konmuştur.
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer that accounts for about 85% of pancreatic tumors. Today, pancreatic cancer has a high mortality rate and the survival rate is very low. Many subtypes of cancer are associated with different levels of aggressiveness because they contain genetically and biologically different mutations, and by their aggressive nature, cancer ranks fourth in mortality statistics. Disruptions in signal mechanisms within the cell result in continuous proliferation and survival. Mutation in the KRAS gene, which plays a role in the development of pancreatic cancer, activates the PI3K / AKT / mTOR signaling pathway associated with cell survival. In addition, the activation loss in CDK2NA and tumor suppressor TP53 in the cell cycle causes uncontrolled cell proliferation. The change of AMPK, which maintains its presence as an energy sensor in the cell and interacts with the cell cycle, plays an important role in the development of cancer aggression.This instability and continuous proliferation in the cell cycle and in the signal pathways interacts with allows the therapeutic efficacy of CDK inhibitors to be improved in cancer treatment. Palbociclib (PD-0332991) and abemaciclib (LY-2835219), which are CDK4 / 6 inhibitors used in the treatment of breast cancer, are important therapeutic agents preferred alone or with combine treatments.Small molecule inhibitors, whose effects are investigated in many types of cancer, are important in the regulation of many signaling mechanisms. In this study, the effects of potential therapeutic competencies on the protein and lipid profiles in the AMPK, which are associated with the application of CDK4 / 6 inhibitors palbociclib and abemaciclib in selected pancreatic cancer cell lines, were investigated. Concluded that metabolic reprogramming is an important feature of cancers that make cancer cells more compatible with different environments and AMPK, which modulates it, has an important role in the decision-making mechanism in this process. In pancreatic cancer, which is known to increase lipid synthesis, suppressing the lipid synthesis process is thought to be an important target for cancer treatment. Reprogramming energy metabolism in cells, it has been demonstrated that CDKi can be a therapeutic target in relation to AMPK lower and upper pathways in pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer that accounts for about 85% of pancreatic tumors. Today, pancreatic cancer has a high mortality rate and the survival rate is very low. Many subtypes of cancer are associated with different levels of aggressiveness because they contain genetically and biologically different mutations, and by their aggressive nature, cancer ranks fourth in mortality statistics. Disruptions in signal mechanisms within the cell result in continuous proliferation and survival. Mutation in the KRAS gene, which plays a role in the development of pancreatic cancer, activates the PI3K / AKT / mTOR signaling pathway associated with cell survival. In addition, the activation loss in CDK2NA and tumor suppressor TP53 in the cell cycle causes uncontrolled cell proliferation. The change of AMPK, which maintains its presence as an energy sensor in the cell and interacts with the cell cycle, plays an important role in the development of cancer aggression.This instability and continuous proliferation in the cell cycle and in the signal pathways interacts with allows the therapeutic efficacy of CDK inhibitors to be improved in cancer treatment. Palbociclib (PD-0332991) and abemaciclib (LY-2835219), which are CDK4 / 6 inhibitors used in the treatment of breast cancer, are important therapeutic agents preferred alone or with combine treatments.Small molecule inhibitors, whose effects are investigated in many types of cancer, are important in the regulation of many signaling mechanisms. In this study, the effects of potential therapeutic competencies on the protein and lipid profiles in the AMPK, which are associated with the application of CDK4 / 6 inhibitors palbociclib and abemaciclib in selected pancreatic cancer cell lines, were investigated. Concluded that metabolic reprogramming is an important feature of cancers that make cancer cells more compatible with different environments and AMPK, which modulates it, has an important role in the decision-making mechanism in this process. In pancreatic cancer, which is known to increase lipid synthesis, suppressing the lipid synthesis process is thought to be an important target for cancer treatment. Reprogramming energy metabolism in cells, it has been demonstrated that CDKi can be a therapeutic target in relation to AMPK lower and upper pathways in pancreatic cancer.
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Keywords
Biyoloji, Genetik, Onkoloji, Biology, Genetics, Oncology