نقش سیکلین ها، کینازهای وابسته به سیکلین و مهارکننده های کینازهای وابسته به سیکلین در چرخه سلولی و سرطان

نوع مقاله : مروری

نویسندگان
مرکز تحقیقات بیماری های غیر واگیر، دانشگاه علوم پزشکی جهرم، جهرم، ایران
چکیده
مقدمه: چرخه سلولی (cell cycle) در پستانداران، یک پروسه بسیار محافظت شده و شامل چهار فاز یا مرحله مشخص است. برای حفاظت از تمامیت ژنوم سلولی، یک سری مکانیسم های وارسی وجود دارد. اختلال در عملکرد مکانیسم های واررسی، باعث القاء سرطان می شود. اختلال در بیان ژن های مهارکننده کینازها بعلت متیلاسیون و یا دِاستیلاسیون باعث القاء سرطان می شود. خوشبختانه این پدیده قابل برگشت است و بیان مجدد ژن های سرکوب گر سرطان، باعث ایجاد آپوپتوز در سلول های سرطانی می شود. در این تحقیق تنظیم گرهای مثبت و منفی چرخه سلولی و استراژی درمانی سرطان به روش اپی ژنتیک مورد بحث و بررسی قرار گرفته است.
روش کار: این مطالعه یک مطالعه مروری نقلی است. اصطلاحات مرتبط شامل سیکلین ها، کینازهای وابسته به سیکلین و ژن های سرکوب کننده سرطان، بعنون کلمات کلیدی، با استفاده از پایگاه های علمی PubMed و Google scholar جستجو و در نهایت مطالعات قابل قبول انتخاب و مورد تجزیه و تحلیل قرار گرفته است.
یافته ها: تغییرات اپی ژنتیک باعث خاموشی ژن های سرکوب کننده سرطان می شوند این تغییرات، باعث تکثیر بی رویه سلول و در نهایت تومورزایی می شود. این تغییرات بوسیله داروهای اپی ژنتیک برگشت پذیر هستند.
نتیجه گیری: داروهای اپی ژنتیک می توانند باعث بیان مجدد ژن های خاموش شده سرکوب کننده سرطان و در نتیجه القاء آپوپتوز شوند. این روش می تواند استراتژی مناسبی برای درمان سرطان باشد.
کلیدواژه‌ها

عنوان مقاله English

The role of cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors on the cell cycle and cancer

نویسندگان English

Masumeh Sanaei
fraidoon kavoosi
Research Center for Noncommunicable Diseases, Jahrom University of Medical Sciences, Jahrom, Iran
چکیده English

Introduction: The mammalian cell cycle is a highly conserved process and contains four distinct ordered phases. There are multiple checkpoint mechanisms to protect genome integrity. Deregulations in these checkpoint mechanisms promote cancer induction. Downregulation of tumor suppressor genes (TSGs) because of DNA methylation and histone deacetylation result in cancer induction. Fortunately, this process is reversible and re-expression of TSGs induce apoptosis induction. In this review, positive and negative cell cycle regulators and therapeutic strategies are investigated.
Methods: This narrative review study has been written with investigation of a series of articles published in the field of cancer. In this work, several keywords were selected from MESH including Cyclin, Cyclin-dependent kinase, cyclin-dependent kinase inhibitors, Tumor suppressor genes, DNA methyltransferase, and Histone deacetylase and search was done using the PubMed online database and the Scholar website. Finally, good and high- quality studies were investigated.
Results: Re-expression of TSGs by epigenetic drugs is suitable strategy for cancer treatment. These compounds can inhibit DNMTs and HDACs activities resulting in re-expression of TSGs.
Conclusion: Epigenetic drugs can reactivate silenced TSGs, resulting in apoptosis induction. This method can be a good strategy for cancer treatment.

کلیدواژه‌ها English

Cyclin
Cyclin-dependent kinase
Tumor suppressor genes
1. Ding L, Cao J, Lin W, Chen H, Xiong X, Ao H, et al. The
roles of cyclin-dependent kinases in cell-cycle progression
and therapeutic strategies in human breast cancer. Int J
Mol Sci. 2020;21(6):1960.
2. Malumbres M. Cyclin-dependent kinases. Genom Biol.
2014;15(6):122.
3. Otto T, Sicinski P. Cell cycle proteins as promising targets
in cancer therapy. Nat Rev Cancer. 2017;17(2):93-115.
4. Asghar U, Witkiewicz AK, Turner NC, Knudsen ES. The
history and future of targeting cyclin-dependent kinases in
cancer therapy. Nat Rev Drug Discov. 2015;14(2):130-46.
5. Csergeová L, Krbušek D, Janoštiak R. CIP/KIP and INK4
families as hostages of oncogenic signaling. Cell Div.
2024;19(1):11.
6. Al Bitar S, Gali-Muhtasib H. The role of the cyclin
dependent kinase inhibitor p21cip1/waf1 in targeting
cancer: Molecular mechanisms and novel therapeutics.
Cancers. 2019;11(10):1475.
7. Velez AMA, Howard MS. Tumor-suppressor genes, cell
cycle regulatory checkpoints, and the skin. North Am J
Med Sci. 2015;7(5):176.
8. Wang L-H, Wu C-F, Rajasekaran N, Shin YK. Loss of
tumor suppressor gene function in human cancer: an
overview. Cell Physiol Biochem. 2019;51(6):2647-93.
9. Geneviève P. Delcuve, Mojgan Rastegar, James R. Davie.
Epigenetic control. J Cell Physiol. 2009; 219: 243–50.
10. Anne C. Mirabella1 & Benjamin M. Foster & Till
Bartke. Chromatin deregulation in disease. Chromosoma
2016; 125:75–93
11. Akone SH, Ntie-Kang F, Stuhldreier F, Ewonkem MB,
Noah AM, Mouelle SEM, et al. Natural products
impacting DNA methyltransferases and histone
deacetylases. Front Pharmacol. 2020;11:992.
12. Qiu T, Zhou L, Zhu W, Wang T, Wang J, Shu Y, et al.
Effects of treatment with histone deacetylase inhibitors in
solid tumors: a review based on 30 clinical trials. Future
Oncol. 2013;9(2):255-69.
13. Tomas Eckschlager, Johana Plch , Marie Stiborova and
Jan Hrabeta. Histone Deacetylase Inhibitors as Anticancer
Drugs. Int J Mol Sci. 2017; 18(7): 1414.
14. van den Heuvel S. Cell-cycle regulation. WormBook:
The Online Review of C Elegans Biology [Internet]. 2005.
15. Malumbres M, Harlow E, Hunt T, Hunter T, Lahti JM,
Manning G, et al. Cyclin-dependent kinases: a family
portrait. Nat Cell Biol. 2009;11(11):1275-6.
16. Suryadinata R, Sadowski M, Sarcevic B. Control of cell
cycle progression by phosphorylation of cyclin-dependent
kinase (CDK) substrates. Biosc Rep. 2010;30(4):243-55.
17. Donjerkovic D, Scott DW. Regulation of the G1 phase
of the mammalian cell cycle. Cell Res. 2000;10 (1):1-16.
18. Schirripa A, Sexl V, Kollmann K. Cyclin-dependent
kinase inhibitors in malignant hematopoiesis. Front Oncol.
2022;12:916682.
19. Quereda V, Martinalbo J, Dubus P, Carnero A,
Malumbres M. Genetic cooperation between p21Cip1 and
INK4 inhibitors in cellular senescence and tumor
suppression. Oncogene. 2007;26(55):7665-74.
20. Starostina NG, Kipreos ET. Multiple degradation
pathways regulate versatile CIP/KIP CDK inhibitors.
Trends Cell Biol. 2012;22(1):33-41.
21. Cánepa ET, Scassa ME, Ceruti JM, Marazita MC,
Carcagno AL, Sirkin PF, et al. INK4 proteins, a family of
mammalian CDK inhibitors with novel biological
functions. IUBMB life. 2007;59(7):419-26.
22. Chim C, Fung T, Wong K, Lau J, Law M, Liang R.
Methylation of INK4 and CIP/KIP families of cyclindependent kinase inhibitor in chronic lymphocytic
leukaemia in Chinese patients. J Clin Pathol.
2006;59(9):921-6.
23. Sanaei M, Kavoosi F. Effect of zebularine in comparison
to and in combination with trichostatin A on CIP/KIP
family (p21Cip1/Waf1/Sdi1, p27Kip1, and p57Kip2),
DNMTs (DNMT1, DNMT3a, and DNMT3b), class I
HDACs (HDACs 1, 2, 3) and class II HDACs (HDACs 4,
5, 6) gene expression, cell growth inhibition and apoptosis
induction in colon cancer LS 174T cell line. Asian Pacific
journal of cancer prevention: Asian Pac J Cancer Prev.
2020;21(7):2131.
24. Feng L-y, Chen C-x, Li L. Hypermethylation of tumor
suppressor genes is a risk factor for poor prognosis in
ovarian cancer: A meta-analysis. Medicine.
2019;98(8):e14588.
25. Turek-Plewa J, Jagodzinski PP. The role of mammalian
DNA methyltransferases in the regulation of gene
expression. Cell Mol Biol Lett. 2005;10(4):631.
26. Ghavifekr Fakhr M, Farshdousti Hagh M, Shanehbandi
D, Baradaran B. DNA methylation pattern as important
epigenetic criterion in cancer. Genet Res Int.
2013;2013(1):317569.
27. Singh V, Sharma P, Capalash N. DNA
methyltransferase-1 inhibitors as epigenetic therapy for
cancer. Curr Cancer Drug Targets. 2013;13(4):379-99.
28. Daniel FI, Cherubini K, Yurgel LS, de Figueiredo MAZ,
Salum FG. The role of epigenetic transcription repression
and DNA methyltransferases in cancer. Cancer.
2011;117(4):677-87.
29. Sanaei M, Kavoosi F. The effect of 5-aza, 2’-
deoxyCytidine (5 AZA CdR or Decitabine) on Extrinsic,
Intrinsic, and JAK/STAT pathways in neuroblastoma and
glioblastoma cells lines. Asian Pac J Cancer Prev.
2023;24(6):1841.
30. Sanaei M, Kavoosi F. Effect of zebularine in comparison
to and in combination with trichostatin A on CIP/KIP
family (p21Cip1/Waf1/Sdi1, p27Kip1, and p57Kip2),
DNMTs (DNMT1, DNMT3a, and DNMT3b), class I
HDACs (HDACs 1, 2, 3) and class II HDACs (HDACs 4,
5, 6) gene expression, cell growth inhibition and apoptosis
induction in colon cancer LS 174T cell line. Asian Pacific
journal of cancer prevention: Asian Pac J Cancer Prev.
2020;21(7):2131.
31. Sanaei M, Kavoosi F, Ghasemi A. Investigation of the
effect of 5-Aza-2’-deoxycytidine on p15INK4, p16INK4,
p18INK4, and p19INK4 genes expression, cell growth
inhibition, and apoptosis induction in hepatocellular
carcinoma PLC/PRF/5 cell line. Adv Biomed Res.
2020;9(1):33.
32. Sanaei M, Kavoosi F. Effect of 5-aza-2'-deoxycytidine
in comparison to valproic acid and trichostatin A on
histone deacetylase 1, DNA methyltransferase 1, and
CIP/KIP family (p21, p27, and p57) genes expression, cell
growth inhibition, and apoptosis induction in colon cancer
SW480 cell line. Adv biomed Res. 2019;8(1):52.
33.Gnyszka A, JASTRZĘBSKI Z, Flis S. DNA
methyltransferase inhibitors and their emerging role in
epigenetic therapy of cancer. Anticancer Res.
2013;33(8):2989-96.
34. Sanaei M, Kavoosi F. Effect of zebularine in comparison
to and in combination with trichostatin A on CIP/KIP
family (p21Cip1/Waf1/Sdi1, p27Kip1, and p57Kip2),
DNMTs (DNMT1, DNMT3a, and DNMT3b), class I
HDACs (HDACs 1, 2, 3) and class II HDACs (HDACs 4,
5, 6) gene expression, cell growth inhibition and apoptosis
induction in colon cancer LS 174T cell line. Asian Pacific
journal of cancer prevention: Asian Pac J Cancer Prev.
2020;21(7):2131.
35. Sanaei M, Kavoosi F. Investigation of the effect of
zebularine in comparison to and in combination with
trichostatin A on p21Cip1/Waf1/Sdi1, p27Kip1, p57Kip2,
DNA methyltransferases and histone deacetylases in colon
cancer LS 180 cell line. Asian Pac J Cancer Prev.
2020;21(6):1819.
36. Cavalli G, Heard E. Advances in epigenetics link
genetics to the environment and disease. Nature.
2019;571(7766):489-99.
37. Dokmanovic M, Clarke C, Marks PA. Histone
deacetylase inhibitors: overview and perspectives.
Molecul Cancer Res. 2007;5(10):981-9.
38.Sanaei M, Kavoosi F. Effect of vorinostat on INK4
family and HDACs 1, 2, and 3 in pancreatic cancer and
hepatocellular carcinoma. Res Pharm Sci. 2021;16(3):260-
8.
39.Sanaei M, Kavoosi F. Effect of valproic acid on the class
I histone deacetylase 1, 2 and 3, tumor suppressor genes
p21WAF1/CIP1 and p53, and intrinsic mitochondrial
apoptotic pathway, pro-(Bax, Bak, and Bim) and anti-(Bcl2, Bcl-xL, and Mcl-1) apoptotic genes expression, cell
viability, and apoptosis induction in hepatocellular
carcinoma HepG2 cell line. Asian Pac J Cancer Prev.
2021;22(S1):89-95.
40. Sanaei M, Kavoosi F. The effect of valproic acid on
intrinsic, extrinsic, and JAK/STAT pathways in
neuroblastoma and glioblastoma cell lines. Res Pharm Sci.
2022;17(4):392-409.