INBRE Supported Research

Cancer comes in many forms, and it can occur in virtually any type of tissue (lung, brain, breast, prostate, blood, etc.). At the molecular level, even cancers of the same tissue type vary greatly from one patient to the next. But one defining feature that is common to all types of cancers is that these cells divide and multiply inappropriately, ignoring the usual constraints that prevent excessive growth. Most cancer chemotherapies attempt to kill the cancer cells outright, but if it were possible to simply stop the tumor cells from multiplying, such an approach might be equally effective. Drugs that block cell division without actually killing the cells might be preferable to current chemo agents, because the new approach would probably produce milder side effects and be better tolerated by patients. We are studying pharmacological agents that cause cells to become senescent. In this state, the cells remain alive, but they produce high levels of p21, p16, and SA- ß-gal, and they are unable to reproduce through cell division.

Left Image: Lung cells multiply until they become tightly packed together.
Middle Image: The same lung cells after treatment with an experimental agent, BeSO4, which blocks cell division without killing the cells.
Right Image: These lung cells were treated with a chemotherapy drug, etoposide, which causes the cells to die.

Lung cells treated with BeSO4 (yellow bars) show a large increase in p21 mRNA compared to untreated control cells (green bars). In contrast, the amount of actin mRNA is unaffected by the drug. p21 is a natural regulator of cell growth that prevents cell division. Actin is a structural protein that is made at a constant rate, so its mRNA is used for normalization and comparison.

Pharmacologically-induced senescence. Replicative senescence is triggered by critically short telomeres, which leads to upregulation of p21, p16, and SA-ß-galactosidase activity. This response can be bypassed by expression of hTERT, the telomerase catalytic subunit. Cell cycle arrest is enforced by p21, which blocks cyclin-dependent kinases (CDK), and p16, which inhibits phosphorylation of Rb. Histone deacetylase (HDAC) inhibitors, such as sodium butyrate and trichostatin A (labeled as I, for inhibitor) can induce a similar state. Be2+ interacts with an unknown receptor target molecule (R) to cause cell cycle arrest and upregulation of p21, p16, and SA-ß-gal. hTERT expression cannot alleviate pharmacologically-induced senescence caused by either class of agent.

Homepage: http://sciences.unlv.edu/Chemistry/gary.htm