Apoptosis (Programmed Cell Death) and the Response to Anticancer Drugs
Earlier studies from Dr. Kaufmann's Anticancer Drug Action Lab provided some of the first biochemical evidence that anticancer drugs induce apoptosis in susceptible cells, that selective protein degradation occurs during this process, and that intracellular cysteine proteases called caspases contribute to this degradation.
Building on these earlier results, current studies in our lab focus on understanding the pathways that lead to caspase activation and the mechanisms that regulate those pathways.
These studies have important implications for understanding why some cancers respond to chemotherapy or immunotherapy and others don't.
One pathway leading to apoptosis, the so-called extrinsic or death receptor pathway, involves tumor cell killing that is initiated by cytotoxic T lymphocytes.
Our research team recently showed that death receptors, which must be present on the cell surface in order for this pathway to be activated, are inhibited from going to the cell surface when the signaling molecule protein kinase C is activated. Conversely, expression of these death receptors is increased by treatment with poly(ADP-ribose)polymerase (PARP) inhibitors.
These observations, which are currently being explored in greater detail, lay the foundation for efforts to increase the efficacy of immunotherapy by modulating the death receptor pathway in various tumors.
The other major pathway leading to apoptosis is the intrinsic, or mitochondrial, pathway.
This pathway is regulated by a family of proteins called BCL2 family members that monitor the intracellular environment and regulate the integrity of mitochondria.
Two of these family members, BAX and BAK, induce cell death by punching holes in the outer mitochondrial membrane, leading to release of mitochondrial proteins to the cytoplasm, where they activate caspases.
Our recent observations, which have focused on BAK, have:
- Provided evidence that other pro-apoptotic BCL2 family members can directly activate BAK, providing new insight into the mechanism of action of a variety of anticancer drugs, including, proteasome inhibitors (bortezomib), NEDD8 activity enzyme inhibitors (MLN4924), mTOR inhibitors (MLN0128), farnesyltransferase inhibitors (tipifarnib), and conventional anticancer drugs such as irinotecan and cytarabine
- Demonstrated that HIV protease can cleave the cellular protein procaspase 8 to an enzymatically inactive fragment that directly activates BAK, providing new insight into HIV-mediated T cell killing
- Showed that BAK undergoes concentration-dependent autoactivation in leukemia and lymphoma cells, providing an explanation for the rapid killing of these cells by so-called BH3 mimetics, such as navitoclax and venetoclax, while simultaneously providing a means to identify cancer cells most susceptible to these agents
Collectively, ongoing studies in the Anticancer Drug Action Lab of apoptotic pathways are designed to provide new insight into factors that govern cancer cell sensitivity to chemotherapy and immunotherapy, while simultaneously elucidating the mechanisms of resistance to a variety of novel anticancer agents.