Antagonizing RARγ Drives Necroptosis of Cancer Stem Cells

Abstract

There is a need for agents that eliminate cancer stem cells, which sustain cancer and are also largely responsible for disease relapse and metastasis. Conventional chemotherapeutics and radiotherapy are often highly effective against the bulk of cancer cells, which are proliferating, but spare cancer stem cells. Therapeutics that target cancer stem cells may also provide a bona fide cure for cancer. There are two rationales for targeting the retinoic acid receptor (RAR)γ. First, RARγ is expressed selectively within primitive cells. Second, RARγ is a putative oncogene for a number of human cancers, including cases of acute myeloid leukemia, cholangiocarcinoma, and colorectal, renal and hepatocellular carcinomas. Prostate cancer cells depend on active RARγ for their survival. Antagonizing all RARs caused necroptosis of prostate and breast cancer stem cell-like cells, and the cancer stem cells that gave rise to neurospheres from pediatric patients' primitive neuroectodermal tumors and an astrocytoma. As tested for prostate cancer, antagonizing RARγ was sufficient to drive necroptosis. Achieving cancer-selectively is a longstanding paradigm for developing new treatments. The normal prostate epithelium was less sensitive to the RARγ antagonist and pan-RAR antagonist than prostate cancer cells, and fibroblasts and blood mononuclear cells were insensitive. The RARγ antagonist and pan-RAR antagonist are promising new cancer therapeutics.

Keywords: cancer stem cells; necroptosis; oncogenes; prostate cancer; retinoic acid receptors.

Figure 1

Patients PCa cells survive and grow in an abnormally low level of ATRA. The low level of ATRA within PCa tissue is important because 0.24 nM ATRA transactivates RARγ, whereas RARα transactivation requires a much higher concentration of 19.3 nM ATRA. Patients’ PCa cells are, therefore, reliant on RARγ transactivation for survival and proliferation. From various studies, active RARγ is pro-survival whereas active RARα is pro-differentiation.

Figure 2

Structures of the RAR agonists and antagonists.

Figure 3

Primary culture of cells from PNET biopsies generates neurospheres with differentiating cells. The cells that give rise to neurospheres are CSCs. Scale bar = 100 μm.