Rolf J. Craven, PhD

1. Keywords: sigma-2 receptor, Pgrmc1, Hpr6, cytochrome, EGFR, autophagy, P450 protein, experimental therapeutics, cancer, RNAi, biomarker

2. Description of research interests: My lab is investigating signaling pathways that are induced in cancer and allow tumor cells to spread and survive outside of their normal environment. Cancer cells often utilize proteins called tyrosine kinases to send pro-growth signals within the tumor, and one of the most frequently activated tyrosine kinases in cancer is called EGFR. We have identified a protein that binds to EGFR and maintains EGFR levels at the plasma membrane. S2R (sigma-2 receptor)/Pgrmc1 (progesterone receptor membrane component 1) was originally identified as a progesterone receptor. However, S2RPgrmc1 is unrelated to steroid hormone receptors and is a cytochrome that binds to heme and forms complexes with EGFR in cancer cells, with cytochrome P450 proteins in normal cells and possibly with an unknown progesterone receptor. Our model is that S2RPgrmc1 helps to process or transport these proteins as they are being synthesized, increasing signaling. S2RPgrmc1 is induced by carcinogenic chemicals as cells start to form tumors. We used the yeast Saccharomyces cerevisiae as a model organism and found that the yeast S2RPgrmc1 homologue provides resistance to chemicals that damage DNA. Remarkably, this function is conserved in humans, because we found that S2RPgrmc1 elevates resistance to DNA damage in cancer cells. This is important for tumors being treated with chemotherapy, and we found that gene therapy blocking S2RPgrmc1 makes cancer cells more sensitive to chemotherapy.

We have also taken several key steps in translating our laboratory research into the clinical setting:

• We found that S2RPgrmc1 is induced in a variety of human tumors, including breast, lung, colon and thyroid tumors, and this result has also been confirmed by a number of other laboratories.

• We have found that S2RPgrmc1 levels correlate with patient survival in lung cancer.

• We identified elevated levels of S2RPgrmc1 in plasma from lung cancer patients, suggesting that its levels may be useful in identifying early stage lung cancer.

• We have shown that S2RPgrmc1 promotes tumor cell growth in culture, as well as anchorage-independent growth, tumor cell invasion, sub-cutaneous tumor growth and tumor metastasis in animals.

• We have found that S2RPgrmc1 elevates the activity of matrix metalloproteinases (MMPs) which increase tumor cell invasion.

• We have identified a small molecule inhibitor of Pgrmc1 that kills tumor cells and disrupts the processing and stability of EGFR.

• A number of groups have previously shown that the sigma-2 receptor is induced in cancers, and the identification of Pgrmc1 as the sigma-2 receptor introduces a spectrum of specific inhibitors that can be tested in cancer cells.

3. Ph.D. received from the University of North Carolina at Chapel Hill, December 1996.

4. Most recent publications:

Rohe, H.J., Ahmed, I.S., Twist, K.E. and Craven, R.J. PGRMC1 (progesterone receptor membrane component 1): a targetable protein with multiple functions in steroid signaling, P450 activation and drug binding. Pharmacology and Therapeutics 121: 14-29 (2009). http://www.sciencedirect.com/science/article/pii/S0163725808001885

Yim, E.-Y., Peng, G., Dai, H., Hu, R., Li, K., Lu, Y., Mills, G.B., Meric-Bernstam, F., Hennessy, B.T., Craven, R.J. and Lin, S.-Y. Rak functions as a tumor suppressor by regulating PTEN protein stability and function. Cancer Cell, 15: 304-314 (2009). http://www.sciencedirect.com/science/article/pii/S1535610809000439

Ahmed, I.S, Rohe, H.A., Twist, K., Mattingly, M. and Craven, R.J. Pgrmc1 (progesterone receptor membrane component 1): a heme-1 domain protein that promotes tumorigenesis and is inhibited by a small molecule. Journal of Pharmacology and Experimental Therapeutics, 333: 564-573 (2010). http://jpet.aspetjournals.org/content/333/2/564.long

Ahmed, I.S., Rohe, H.J., Twist, K.E. and Craven, R.J. Pgrmc1 (progesterone receptor membrane component 1) associates with EGFR and regulates erlotinib sensitivity, Journal of Biological Chemistry, 285: 24775-24782 (2010). http://www.jbc.org/content/285/32/24775.long

Mallory, J.C. and Craven, R.J. Candida albicans Dap1p promotes ergosterol synthesis via the P450 protein Erg11p/Cyp51p, regulating susceptibility to azole antifungal drugs, morphogenesis and damage resistance. Pharmacologia 3: 179-189 (2011). http://docsdrive.com/pdfs/pharmacologia/2012/179-189.pdf

Ahmed, I.S., Chamberlain, C. and Craven, R.J. S2RPgrmc1: the cytochrome-related sigma-2 receptor that regulates lipid and drug metabolism and hormone signaling. Expert Opinion on Medicinal Chemistry and Toxicology, 8: 361-370 (2012). http://informahealthcare.com/doi/abs/10.1517/17425255.2012.658367

Mir, S.U.R., Ahmed, I.S., Arnold, S. and Craven, R.J. Elevated Pgrmc1 (progesterone receptor membrane component 1)/sigma-2 receptor levels in lung tumors and plasma from lung cancer patients. International Journal of Cancer 131: 1-9 (2011). Breuer, E.-K. Y., Murph, M.M. and Craven, R.J. Biochemical Pathways in Cancer. Biochemistry Research International. 2012: 268504 (2012).

Mir, S.U.R., Jin, L. and Craven, R.J. Ngal (neutrophil gelatinase-associated lipocalin) transcription dependent on the tumor-associated sigma-2 receptor S2RPgrmc1. Journal of Biological Chemistry, 287: 14494-14501 (2012).

Ahmed, I.S., Chamberlain, C. and Craven, R.J. S2RPgrmc1: the cytochrome-related sigma-2 receptor that regulates lipid and drug metabolism and hormone signaling. Expert Opinion on Medicinal Chemistry and Toxicology, 8: 361-370 (2012).

Jin, L. and Craven R.J. The Rak/Frk tyrosine kinase associates with and internalizes the epidermal growth factor receptor. Oncogene, in press. Mir, S.U.R., Schwarze, S., Jin, L., Zhang, J. Friend, W., Miriyala, S., St Clair, D. and Craven, R.J. Sigma-2 receptor associates with MAP1-LC3B and promotes autophagy. Autophagy, in press. 5.

Present and recent members of the lab:

Ling Jin, Technician

Steve Schwarze, Researcher

Breanna Grubb, Student

Kaia Hampton, PhD