Understanding, diagnosing, and treating pancreatic cancer from the perspective of telomeres and telomerase

Abstract

Telomerase is associated with cellular aging, and its presence limits cellular lifespan. Telomerase by preventing telomere shortening can extend the number of cell divisions for cancer cells. In adult pancreatic cells, telomeres gradually shorten, while in precancerous lesions of cancer, telomeres in cells are usually significantly shortened. At this time, telomerase is still in an inactive state, and it is not until before and after the onset of cancer that telomerase is reactivated, causing cancer cells to proliferate. Methylation of the telomerase reverse transcriptase (TERT) promoter and regulation of telomerase by lactate dehydrogenase B (LDHB) is the mechanism of telomerase reactivation in pancreatic cancer. Understanding the role of telomeres and telomerase in pancreatic cancer will help to diagnose and initiate targeted therapy as early as possible. This article reviews the role of telomeres and telomerase as biomarkers in the development of pancreatic cancer and the progress of research on telomeres and telomerase as targets for therapeutic intervention.

Fig. 1. Telomerase presence and telomere maintenance in the pancreas.

The development of telomerase expression and telomere length are displayed in the context of health and disease. Telomeres are the DNA Protein structure at the end of chromosomes. Telomeres are synthesized by telomerase, and the activity of telomerase in the infant’s pancreas is strong, which promotes the proliferation of healthy pancreatic cells. In adulthood or after illness, exposure to adverse sleep habits, diseases, and other risk factors can induce inflammation, oxidative stress, and cell death [155]. Subsequently, the pancreas maintains its function through cell renewal, but this process can lead to telomere shortening. The shortening of telomeres to a certain length may be the fundamental reason for cell division reaching the Hayflick limit, during which cells undergo replication aging, leading to DNA damage response (DDR) and cell senescence. Before and after pancreatic cancer, telomerase is reactivated, and telomeres are maintained at a certain length, which allows pancreatic cancer cells to escape from replicative senescence and make pancreatic cancer continue to develop.

Fig. 2. The vertebrate telomere complex.

The telomere has a T-loop and D-loop structure, which is divided into 3 ‘and 5’ ends at the end. There is a Shelterin complex on the telomeres, which helps maintain stability. POT1 protection of telomeres 1. RAP1 repressor/activator protein 1. TIN2 TERF1-interacting nuclear factor 2. TPP1 telomere protection protein 1. TRF1 telomeric repeat binding factor 1. TRF2 telomeric repeat binding factor 2.

Fig. 3. The vertebrate telomerase complex.

The composition of human telomerase is divided into three parts: TERT, TEN, and Cofactor. They combine together to form telomerase, maintaining the length of telomeres. GAR1 nucleolar protein family A. member 1. NHP2 nucleolar protein family A, member 2. NOP10 nucleolar protein 10. TCAB1 telomerase Cajal body protein 1.

Fig. 4. The activation mechanism of telomerase.

A Loss or methylation of gene fragments on chromosomes. B Increase in LDHB protein. C The interaction between GOLPH3 and STIP1 increases the expression of c-MYC.

Fig. 5. Common treatment methods targeting telomerase and telomerase.

A Telomerase vaccines can recognize TERT peptides on the surface of cells with high TERT levels, thereby promoting the killing of CD4 + T and CD8 + T cells. The oncolytic virus can selectively replicate and lyse cells in cells activated by telomerase. B Small molecule inhibitor BIBR1532 can bind to TERT or TER, prevent the binding between TERT and TER, and inhibit the formation of telomerase. C The oligonucleotide inhibitor imetelstat can compete with telomeres and bind to TER, thereby preventing the binding between telomeres and telomerase. D CDDO Me can weaken hTERT mRNA, basal hTERT, phosphorylated hTERT, and methylation of hTERT promoter, thereby reducing telomerase activity. E G-quadruplex stabilizers can stabilize the G-quadruplex structure of telomeres, prevent DNA helicase from degrading them, and block the telomere elongation process.