MDA7IL24 INDUCES CELL DEATH IN NEUROBLASTOMA THROUGH A

MDA-7/IL-24 INDUCES CELL DEATH IN NEUROBLASTOMA THROUGH A NOVEL MECHANISM INVOLVING AIF AND ATM Translated by Krishna Karamsetty

INTRODUCTION Neuroblastoma is type of cancer that affects the central nervous system in children under 5 years of age. When neuroblastoma shows up as a tumor, it presents as a heterogenous mass and regular cancer treatments are often painful and ineffective towards the patient. There are other forms of therapy such as chemotherapy and radiotherapy and immunotherapy but this paper mainly deals with gene therapy. To combat this situation, the researchers in this article created a new form of treatment for this dangerous form of cancer.

WHAT IS THIS NEW FORM OF THERAPY? Gene therapy is a relatively new form therapy and this article deals with the gene MDA-7 as a new form of gene therapy. In a cancer cell, MDA-7 is absent. Since it is absent, the researchers had to find a way to make it expressed in the cancer. They did this by making a genetically modified virus to specifically target cancer cells. If MDA-7 enters into a normal cell, it doesn’t harm the health cell.

THE VIRUS In order for this virus to work specifically on cancer cells, four parts are needed: Adenoviral gene, E 1 A, PEG-3 and MDA-7. E 1 A is a gene that is found inside viruses which allows them to replicate. PEG-3 is a gene that works as a cancer radar. Normal cells don’t have as much PEG-3 as cancer cells. When the PEG -3 in the virus detects PEG outside, it allows it to select the cancer cells.

VIRUS+MDA-7 STOP CELL GROWTH This experiment was done to show that the virus and MDA-7 were stopping cell growth as time went along. Where the cells were infected with the virus + MDA-7, the higher the dose and the more time, the more effective the treatment was.

VIRUS+MDA-7 DOESN’T USE NORMAL CANCER KILLING PATHWAYS We know that apoptosis is induced by a family of proteins called caspases. However, when they went to go check for caspase activity, it was surprisingly absent. In order for caspase activity to be determined, there must be two lines of blots instead of one. However, row 1 only has caspase activity under the toxic chemical, not under anything with MDA-7.

VIRUS+MDA-7 CAUSES CELL DEATH IN NEUROBLASTOMA So how exactly is the gene causing cell death in these cancer cells. MDA-7 is using a protein known as AIF or apoptosis inducing factor. This protein works separately from caspases. Where the virus + MDA-7 is present, AIF is more pronounced in the cells which shows up as the red fluorescence.

VIRUS+MDA-7 WORKS INSIDE LIVE SUBJECTS AS WELL In the previous experiments, all the experiments were done in petri dishes. So in order to show that the treatment works in a live subject, nude mice were first implanted with neuroblastoma tumor cells on the left and right sides and allowed them to grow. Then the tumor cells were infected with the treatment. In the TUNEL Assay, where there is more color, it means there’s more cell death. This also shows that although the left side was injected there is also cell death on the right side.

FUTURE PLANS Since the experiments were done in immuno-compromised animals, there was nothing stopping the virus from doing its job. The next step is to test the viruses in immune-competent mice.

REFERENCES P Bhoopathi, N Lee, A Pradhan, X Shen, S Das, D Sarkar, L Emdad, P Fisher (2016) mda-7/IL 24 Induces Cell Death in Neuroblastoma through a Novel Mechanism Involving AIF and ATM, Cancer Research, June 2016 76: 12 Jiang H, Lin JJ, Su ZZ, Goldstein NI, Fisher PB. Subtraction hybridization identifies a novel melanoma differentiation associated gene, mda-7, modulated during human melanoma differentiation, growth and progression. Oncogene 1995; 11: 2477“ 86. Sarkar D, Su ZZ, Vozhilla N, Park ES, Gupta P, Fisher PB. Dual cancer-specific targeting strategy cures primary and distant breast carcinomas in nude mice. Proc Natl Acad Sci U S A 2005; 102: 140349.