Targeting radiation induced neuroendocrine differentiation as a novel approach in prostate cancer therapeutics

Christopher Suarez, Purdue University

Abstract

Despite significant advances in better treating and managing prostate cancer, challenges remain in understanding and developing treatments for recurrent onset of the disease. One possible mechanism, involving the pathway to recurrence, is the transdifferentiation process, by which prostate cancers differentiate into neuroendocrine-like cells, also known as neuroendocrine differentiation (NED). NED has been associated with progression of prostate cancer, androgen-independent growth and poor prognosis. We previously reported that fractionated ionizing radiation (IR) induces NED. Dedifferentiation of these neuroendocrine-like cells gives rise to a population that has become resistant to chemotherapeutic agents and further IR induced cell death. In addition, we found that IR induced NED is associated with increased CREB phosphorylation. To examine the role of CREB in IR-induced NED, two approaches were utilized. A lentiviral short-hairpin (shRNA) approach was utilized to create tetracycline-inducible stable cell lines knocking down CREB and a separate tetracycline-inducible expression system was utilized to express a dominant negative CREB named acidic CREB, or ACREB. We found that knockdown of CREB in LNCaP cells decreased IR-induced neurite extension and expression of NSE after a 40 Gy cumulative dose. Likewise, expression of ACREB increased sensitivity to IR after a fractionated dose of 10 Gy. Additionally, we observed that IR treatment of LNCaP cells can be broken down into two unique phases. The first phase occurs during the initial two weeks of fractionated IR treatment and is associated with the acquisition of radioresistance. Only those cells able to acquire radioresistance progress to the next phase involving the acquisition of NED. Interestingly, knockdown of CREB was sufficient to inhibit IR-induced neurite extension, but did not have an apparent effect on IR-induced cell death during the first two weeks. On the other hand, expression of ACREB, which can bind all CREB/ATF1 family transcription factors and almost completely knockdown CREB expression, sensitized 34% of cells to IR during the first week. Taken together, we provide evidence that targeting CREB signaling, by inhibiting both the radioresistance and NED phases, is an attractive strategy for prostate cancer radiotherapy.

Degree

Ph.D.

Advisors

Hu, Purdue University.

Subject Area

Molecular biology|Biochemistry|Oncology

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