Thomas Jefferson University

Novel Signaling Pathway in Drug Resistant Prostate Cancer

Specific integrin promotes cell growth and survival of castrate-resistant prostate cancer through novel pathway – potential new target for cancer drug development.

Treatment strategies for prostate cancer most commonly include drugs that greatly reduce the level of testosterone, an androgen hormone. The drugs are effective because the low levels of testosterone, similar to levels achieved by castration, are inadequate to bind and activate the Androgen Receptor, a protein that fuels prostate cancer growth and survival. Yet, some prostate cancers become resistant to these drug therapies, often by activating the Androgen Receptor via a different mechanism.  Investigating just how cancer cells become resistant, Jefferson researchers recently identified a novel pathway capable of restoring Androgen Receptor activity to prostate tumor cells that have reduced testosterone levels.   

“This novel pathway may provide new strategies to treat prostate cancer, especially castrate-resistant prostate cancer,” says Lucia Languino, Ph. D., Professor in the Department of Cancer Biology at Thomas Jefferson University and researcher at the Sidney Kimmel Cancer Center at Jefferson.  Dr. Languino and her colleagues at Jefferson, including first author Dr. Huimin Lu, recently published their findings in Cancer Research. Additional co-authors and collaborators included researchers from the University of Massachusetts Medical School, The Wistar Institute, Yale University, Biogen Inc., and the University of Virginia.    

Dr. Languino explains, “Cancer cells sometimes increase production of one or more proteins, and occasionally, at increased levels, one of those proteins will assume a new function within the cell – one that restores tumor cell growth even in the presence of a cancer drug.  In our study, we showed that avb6 integrin receptor, when produced at higher than normal levels, restored activity of the Androgen Receptor to promote growth and survival of tumor cells, even in the absence of testosterone.”

Researchers already knew that some types of cancer produce the avb6 integrin at high levels, and that avb6 integrin plays a role in cancer survival and metastasis. However, their work was the first to demonstrate a connection between avb6 integrin and Androgen Receptor activation in prostate cancer.

Dr. Languino and her colleagues further determined just how avb6 integrin was performing this new function. Typically, binding of avB6 integrin to a binding partner or ligand results in a step-wise cascade of protein activation events – known as a signaling pathway – to ultimately turn on expression of particular gene or set of genes. Yet, none of the avb6 integrin-mediated signaling pathways were known to result in activation of the Androgen Receptor.

The researchers showed that in prostate cancer cells, avb6 integrin expression caused activation of a downstream protein kinase called JNK1, which in turn caused activation of the Androgen Receptor.  They also determined that the JNK1-activated Androgen Receptor moved into the cancer cell’s nucleus, where it turned on expression of a gene called survivin – confirming an already established role for survivin in prostate cancer cell survival and resistance to therapy. Finally, the researchers ruled out the participation of several other kinases and pathways; they

Novel Signaling Pathways

showed that the effect was specific to avb6 integrin, and did not occur with a different integrin.

Dr. Languino and her colleagues also examined prostate cancer tissue specimens for the presence of avb6 integrin and survivin. They detected expression of avb6 integrin in 35 out of 47 prostate cancer specimens, but not in 8 out of 8 normal prostate specimens. In addition, the researchers detected co-expression of survivin and avB6 integrin in 34 specimens.

“When cancer cells develop resistance to drug therapies, it is critical that additional drugs are available to effectively treat the cancer. Pinpointing alternative signaling pathways that enable cancer cells to become drug resistant is key to new drug discovery efforts. Our studies – which identified a novel signaling pathway linking avb6 -integrin expression to Androgen receptor activity – suggest that the avb6 integrin may be a target for the development of new drugs to fight advanced prostate cancer,” says Dr. Languino.

Citation:  Lu, H; Wang, T; Li, J; Fedele, C; Zhang, J; Jiang, Z; Jain, D; Iozzo, RV; Violette, SM; Weinreb,, PH; Davis, RJ; Gioeli, D; FitzGerald, TJ; Altieri, DC; Languino, LR. “avb6 Integrin Promotes Castrate-Resistant Prostate Cancer through JNK1-Mediated Activation of Androgen Receptor.” Cancer Research, 2016; 56(17); 5163-74 DOI: 10.1158/0008-5472.CAN-16-0543

Funding Statement:  This work was supported by NIH CA89720 and CA109874 to L.R.L., CA78810 and CA90917 to D.C.A., CA140043 to L.R.L. and D.C.A., CA65861 to R.J.D., CA39481 to R.V.I., Danny Cancer Funds P00010003300000 to T.W., P60010008300000 to J.L., Postdoctoral Research Fellowship from the American Italian Cancer Foundation to C.F.  This project was also funded, in part, under a Commonwealth University Research Enhancement Program grant with the Pennsylvania Department of Health (H.R.); the Department specifically disclaims responsibility for any analyses, interpretations or conclusions.

Conflict of Interest:  S.M. Violette and P.H. Weinreb have ownership interest (including patents) at Biogen, Inc.  The other authors disclosed no potential conflicts of interest.

 

By:  Deb Roussell, Ph. D.