By Linya Thng
In a time where premature deaths by COVID-19 are common, it is important to remember that our fight against cancer, the second highest cause of death in humans today, continues. Although the figure is half that of cardiovascular disease, cancer kills 8.93 million people annually – more than the next 3 causes combined. Although there is no known cure for cancer where all traces of cancer cells are eliminated within the body, modern medicine does allow for remission or complete remission where there are no longer detectable signs of cancer symptoms. A primary method to achieve this is chemotherapy.
Chemotherapy induces DNA damage, which leads to cell death, and is designed to halt cancer by causing cells to enter a non-dividing state, senescence. However, under non-lethal doses, surviving cells would acquire either a proliferative or senescent phenotype. Senescence in normal cells promotes tissue degeneration and ageing, whilst cancer-therapy-induced senescence is often associated with positive clinical outcomes (Hsu, Altschuler & Wu, 2019). The cyclin-dependent kinase inhibitor p21 is a key promoter after chemotherapy exposure. Studying the dynamics of protein p21 helps us understand the control of chemotherapy-induced entry into senescence. The factors driving the senescence of tumour cells play a vital role in the development of new anticancer treatments.
It is difficult to determine the success of chemotherapy alone as it is usually given as a treatment alongside others, such as radiotherapy and, in more severe cases, surgery. However, it is important to understand that chemotherapy effectiveness is influenced by a number of factors such as cancer stage, cancer metastasis, cancer grade, the abnormality of cancer cells (more abnormal cells spread quicker), as well as age, health and hereditary factors. A study, by the University of Paris in September 2006, was conducted on 761 tumours of non-small-cell localized lung cancers and showed that post-surgery chemotherapy patients had a 4.1% higher 5-year survival rate than non-chemo patients. However, just under half of the patients in the study (44%) carried the ERCC1 gene, linked to chemo-resistance, as it is known to repairs cancer cell DNA. Of the patient sample that did not carry the ERCC1 gene, the 5-year survival rate increased with 8% compared to non-chemo patients (39% versus 47% of those who did undergo chemo treatment) (Olaussen et al., 2006). ERCC1 deficiency leads to an increase in expression of cyclin-dependent kinase inhibitor p21, increasing the effectiveness of chemotherapy. But what is the mechanism between the success of chemotherapy and the inhibitor p21?
In normal cells, the protein p21 functions as an anti-proliferative effector and cell cycle inhibitor, specifically in cell cycle arrest involving p53 transcription factor activity. Cancer-speaking, p21 plays an imperative role in blocking cell division by inhibiting protein complexes known as cyclin-dependent kinases. In the scenario of damaged DNA, p21 activity delays cell division and growth, allowing more time for DNA repair to prevent further cellular ramifications (Tremblay et al., 2015). Some studies suggest p21 induces senescence during chemotherapy, whilst others suggest the protein promotes cell-division after chemotherapy. These clashes can only imply that the abundance and dynamics of p21 after chemotherapy are crucial for determining the fate of cancer cells: entering senescence or cell division.
Cancer cells can choose to either remain proliferative or become senescent when experiencing non-lethal doses due to a decline in drug concentrations – the cell fate shows bistability. The cell’s decision is made by its underlying design principles, where the dynamics of the protein p21 are analysed by comparing the distinct patterns of the early dynamics of p21 to the final cell fate. While high p21 expression is generally associated with senescence, we would expect the opposite during drug treatment at earlier stages – most senescence-fated cells appear in lower levels than proliferation-fated cells. The protein results in a p21 “Goldilocks zone” which suggests that an increase in p21 expression can lead to an undesirable increase of cancer cell proliferation (Hsu, Altschuler & Wu, 2019). The “Goldilocks zone” is defined by the dynamic regulation of p21 expression and DNA damage – determining whether cells would divide after chemotherapy.
Understanding the processes that govern the fate of cancer cells after chemotherapy is the first step towards a potential cancer cure. The next step is to determine strategies that maximize the effectiveness of our current anticancer agents. Studies suggest targeting the G1/S checkpoint can prevent the proliferation of cancer cells that survive chemotherapy. Future cancer treatments can be improved by the identification of drug combinations that avoid tumour relapse due to proliferating cells.
Hsu, C., Altschuler, S. J. & Wu, L. F. (2019) Patterns of Early p21 Dynamics Determine Proliferation-Senescence Cell Fate after Chemotherapy. Cell (Cambridge). 178 (2), 361-373.e12. Available from: doi: 10.1016/j.cell.2019.05.041.
Olaussen, K. A., Dunant, A., Fouret, P., Brambilla, E., André, F., Haddad, V., Taranchon, E., Filipits, M., Pirker, R., Popper, H. H., Stahel, R., Sabatier, L., Pignon, J., Tursz, T., Le Chevalier, T. & Soria, J. (2006) DNA Repair by ERCC1 in Non–Small-Cell Lung Cancer and Cisplatin-Based Adjuvant Chemotherapy. The New England Journal of Medicine. 355 (10), 983-991. Available from: doi: 10.1056/nejmoa060570.
Tremblay, C. S., Saw, J., Chiu, S. K. & Curtis, D. (2015) Overcoming quiescence by targeting p21 (Cdkn1a) sensitizes pre-leukemic stem cells to chemotherapy. Experimental Hematology. 43 (9), S45. Available from: doi: 10.1016/j.exphem.2015.06.050.