Rolf J. Craven, Ph.D.

Associate Professor;
University of North Carolina at Chapel Hill 1996

Office: 213 Combs Cancer Research Building (0096)
Lab: (859) 323-5050
Tel: (859) 323-3832

Rolf.Craven@uky.edu

Current 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) a.k.a.Hpr6 (human membrane progesterone receptor) was originally identified as a progesterone receptor, but it is unrelated to steroid hormone receptors. Instead, S2RPgmrc1 is a cytochrome that binds to heme and forms a complex with EGFR in cancer cells and with cytochrome P450 proteins in normal cells. Our model is that S2RPgmrc1 helps to process or transport EGFR as it is being synthesized, increasing EGFR signaling in tumor cells.

S2RPgmrc1 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 S2RPgmrc1 homologue provides resistance to chemicals that damage DNA. Remarkably, this function is conserved in humans, because we found that S2RPgmrc1 elevates resistance to DNA damage in cancer cells. This is important for tumors being treated with chemotherapy, and we found that gene therapy blocking S2RPgmrc1 makes cancer cells more sensitive to chemotherapy.

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

We were the first to show that S2RPgmrc1 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 S2RPgmrc1 levels correlate with patient survival in lung cancer.
We identified elevated levels of S2RPgmrc1 in plasma from lung cancer patients, suggesting that its levels may be useful in identifying early stage lung cancer.
We have shown that S2RPgmrc1 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 S2RPgmrc1 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.
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.

Selected Publications

Craven, R.J., Mallory, J.C., and Hand, R.A.
Regulation of iron homeostasis mediated by the heme-binding protein Dap1 (damage resistance protein 1) via the P450 protein Erg11/Cyp51.
Journal of Biological Chemistry 282: 36543-36551 (2007) PMID: 17954932.

Craven, R.J.
PGRMC1: a new biomarker for estrogen-responsive breast cancers.
Breast Cancer Research 10: 113-114 (2008) PMID: 19090968.

Yang, M.M., Jarrett, S.J., Craven, R. and Kaetzel, D.M.
YNK1, the yeast homolog of human metastasis suppressor NM23, is required for repair of UV radiation- and etoposide-induced DNA damage.
Mutation Research 660: 74-79 (2009) PMID: 18983998.

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) PMID: 18992768.

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) PMID: 19345329.

Dietrich CS, Greenberg VL, DeSimone CP, Modesitt SC, van Nagell JR, Craven R., Zimmer SG.
Suberoylanilide Hydroxamic Acid (SAHA) Potentiates Paclitaxel-Induced Apoptosis in Ovarian Cancer Cell Lines.
Gynecologic Oncology, 116: 126-130 (2010) PMID: 19875160.

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) PMID: 20164297.

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) PMID: 20538600.

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, in press.

Present and recent members of the lab

Shakeel Mir, Post-doctoral fellow
Ling Jin, Technician
Steve Schwarze, Researcher
Cora Chamberlain, Undergraduate student
Matthew Thacker, Technician
Hannah Rohe, Medical student
Ikhlas Said Ali Ahmed, Graduate student

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