Self-destructive Cancer: Tricking Tumors Into Targeting Themselves

Reading time: 3 minutes

Aya Elmeligy

When you think of cancer treatment you might think of aggressive chemotherapy, intense radiation, and endless drugs which all carry the risk of damaging healthy cells in addition to the cancerous ones. But ultimately, it is all worth it to hear the words “You are cancer free!”. But what if we could change this approach? Here we discuss three research studies that utilized various biological processes to target cell death in only cancerous cells: using E2F transcription factors, triggering a form of cell death called apoptosis or by using small RNA molecules.

Researchers are looking at possibly triggering cell death in just the tumor cells while protecting the healthy cells. Transcription factors drive the proliferation of cells. One group in particular, called E2Fs are key regulator in the cell cycle and drive this cell cycle progression in healthy and cancerous cells. In most human malignancies, dysregulation of the transcription factor E2F-1 is frequent. Research has demonstrated that E2F-1 can both promote cellular proliferation and programmed cell death (known as apoptosis), possessing both tumor-promoting and tumor-suppressive effects. Many growth-inducing E2F target genes have been identified. However, the pathways for apoptosis are less obvious and more complicated (1). Mutant mouse models have shown that overexpression of E2F-1 leads to cell death through various mechanisms, either by inhibiting anti-apoptotic signaling such as NF-κB activation or stabilizing levels of the p53 tumor suppressor gene. However, these pathways are not completely understood and ultimately will require further research to provide conclusive results.

The body has its own defense line when it comes to restricting rapid unnecessary growth. Apoptosis is an example of programmed cell death that is triggered by the body; unfortunately, this is severely affected in cancers as the cancer cells resist signals for apoptosis. The downside of this is uncontrolled growth due to irregular control of cell death and proliferation. Apoptosis works by activating a protein called procaspase-3 to become caspase-3, which kickstarts this programmed cell death. This process is induced by the release of mitochondrial cytochrome c. Extraordinary research by a team led by Paul Hergenrother trialed 20,000 different synthetic molecules to initiate apoptosis in tumor cells; one success was with a molecule called ‘Procaspase Activating Compound Number One’ (PAC-1). This success was dependent on the already available levels of procaspase-3 within the body. The research showed apoptosis of colon cancer cells in vitro and depletion in the growth of the tumor in mouse models.  Mouse lungs had high levels of pro-caspase-3, and therefore, the therapy was effective. This indicated that a personalized approach can be taken with this treatment depending on a patient’s pro-caspase-3 levels (2). 

MicroRNAs are small sections of RNA that can be used for a process known as RNA interference (RNAi). MicroRNA-like small interfering RNAs (siRNAs) can be produced to target and decrease levels of proteins in specific RNAs. These siRNAs are created by turning short segments of the target gene into double-stranded RNA; when reintroduced into cells, this RNA suppresses the expression of the gene from which it was originally produced. Two proteins were identified as targets for RNAi experimentation, CD95, and CD95L. Both of these have been implicated in human cancers and although their mechanism of action is not yet known their dysregulation via RNAi resulted in cell death in different cancer cell lines (3). Provided further experimentation shows the same result then future prospects would look at shrinking tumors in animal models of cancer, possibly resulting in a new cancer treatment.

These examples of research provide insight into the possible therapies that may be easier for the patient than traditional treatments that can lower the quality of life. Further studies in these areas could lead to breakthroughs that could be used for clinical applications.

Edited by Shreyas Gaikwad


  1. Bell, L.A. and Ryan, K.M. (2003). Life and death decisions by E2F-1. Cell Death & Differentiation, 11(2), pp.137–142. doi:10.1038/sj.cdd.4401324.
  2. ‌Putt, K.S., Chen, G.W., Pearson, J.M., Sandhorst, J.S., Hoagland, M.S., Kwon, J.-T., Hwang, S.-K., Jin, H., Churchwell, M.I., Cho, M.-H., Doerge, D.R., Helferich, W.G. and Hergenrother, P.J. (2006). Small-molecule activation of procaspase-3 to caspase-3 as a personalized anticancer strategy. Nature Chemical Biology, 2(10), pp.543–550. doi:10.1038/nchembio814.
  3. Putzbach, W., Gao, Q.Q., Patel, M., van Dongen, S., Haluck-Kangas, A., Sarshad, A.A., Bartom, E.T., Kim, K.-Y.A., Scholtens, D.M., Hafner, M., Zhao, J.C., Murmann, A.E. and Peter, M.E. (2017). Many si/shRNAs can kill cancer cells by targeting multiple survival genes through an off-target mechanism. eLife, 6. doi:10.7554/elife.29702.
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