Radiation-induced signal transduction and regulation of apoptosis in solid tumors

The process of growth inhibition and apoptosis require coordinate expression of specific genes. Cellular proliferation is a complex process involving both stimulatory and inhibitory signals.  Abnormal proliferation observed in cancer cells is caused by mutations that either increase positive signals or decrease negative growth control signals or both. Thus, for a cancer cell to respond to chemotherapy or radiation therapy, genes regulated during growth inhibition and apoptosis needs to be functional.  However, most tumors acquire genetic mutation in these key regulatory genes disrupting either one or both of these pathways.  This allows a tumor cell to acquire resistance to cell-killing agents and thus poses an important challenge in controlling these aggressive tumors.  Gene expression studies revealed that there exists more than one pathways regulating growth inhibition and apoptosis processes.  The few important pathways include: (1) pathways mediated through transcription factors (such Egr-1 and p53) to induce cell cycle arrest and apoptosis; (2) pathway mediated through TGF-b signaling for negative growth regulation; and (3) pathways downstream to p53 and TGF-b acting as cross-point regulators that can induce, enhance, delay or inhibit apoptosis (bcl-2, bax, par-4 etc).The process of growth inhibition and apoptosis require coordinate expression of specific genes. Cellular proliferation is a complex process involving both stimulatory and inhibitory signals.  Abnormal proliferation observed in cancer cells is caused by mutations that either increase positive signals or decrease negative growth control signals or both. Thus, for a cancer cell to respond to chemotherapy or radiation therapy, genes regulated during growth inhibition and apoptosis needs to be functional.  However, most tumors acquire genetic mutation in these key regulatory genes disrupting either one or both of these pathways.  This allows a tumor cell to acquire resistance to cell-killing agents and thus poses an important challenge in controlling these aggressive tumors.  Gene expression studies revealed that there exists more than one pathways regulating growth inhibition and apoptosis processes.  The few important pathways include: (1) pathways mediated through transcription factors (such Egr-1 and p53) to induce cell cycle arrest and apoptosis; (2) pathway mediated through TGF-b signaling for negative growth regulation; and (3) pathways downstream to p53 and TGF-b acting as cross-point regulators that can induce, enhance, delay or inhibit apoptosis (bcl-2, bax, par-4 etc). 

Treatment strategies such as chemotherapy and radiation eliminate malignant cells by the induction of apoptosis as well as by "mitotic death".  For example, therapeutic ionizing radiation can cause DNA strand breakage or distortion of the DNA nucleoprotein conformation which may transduce signals that result in activation of early response genes (c-jun, c-fos and Egr-1) whose gene products may then stimulate later genes. These later genes (TNF-a, TGF-b, p53) are important in cellular response to radiation injury (such as cell death).  To understand the impact of "complex dysregulated gene alterations" on radiation response, Dr Ahmed focused his research on three important pathways: (1) Early gene transcription factor ?Egr-1? mediated regulation of radiation-induced apoptosis; (2) TGF-b signaling pin radiation response, (3) Effect of Low Dose Fractionated Radiation in combination with chemotherapy on bcl2 expression and NFkB activity.  The tumor system used in research area 1 is prostate cancer, the tumor systems used in research area 2 is pancreas and lung cancer, and the tumor systems used in the area 3 is head & neck, ovarian, lung and pancreas cancers. signaling in the regulation of radiation response; and (3) Effect of low-dose fractionated radiation in combination with chemotherapy on bcl-2 expression and NFkB activity.  The tumor system used in research area 1 is prostate cancer, the tumor systems used in research area 2 is pancreas and lung cancer, and the tumor systems used in the area 3 is head & neck, ovarian, lung and pancreas cancers.