Researchers explain mechanism of aggressive prostate cancer

February 8, 2020 0 By FM

A team of researchers led by Dr. Bushra Ateeq from the Indian Institute of Technology (IIT) Kanpur has explained the underlying mechanism behind the aggravation of prostate cancer after using androgen deprivation drugs, in a recent study. The team also demonstrates a safe alternative that could help reduce prostate cancer growth at an aggressive stage.

Androgen deprivation drugs used in treating prostate cancer acts by inhibiting the production of androgen or testosterone and/or androgen signalling in the patient to prevent the growth of prostate cancer cells.

However, in certain cases the drug may unintentionally aid the cancer cells to become resistant to the therapy, which results in the progression of cancer to its lethal forms.

The authors noted that inhibiting androgen signalling using anti-androgen drugs, increased the levels of SPINK1protein, which makes the cancer cells more aggressive. SPINK1 protein is generally found associated with an aggressive type of prostate cancer present in 10-25% of the patients.

The aggressive subtype of prostate cancer known as neuroendocrine prostate cancer (NEPC) is found to arise de novo or as a mechanism of resistance due to anti-androgen therapy.

The team on administering anti-androgen drugs (enzalutamide and apalutamide) into mice implanted with prostate cancer cell lines observed an increase in the expression of SPINK1 gene.

The tumours isolated from the mice also showed elevated levels of the protein as well as markers for neuroendocrine prostate cancer, which triggered a change in cellular plasticity resembling the aggressive form of cancer observed in patients.

The study revealed that androgen receptor (AR) functions as a repressor of the SPINK1 gene. Thus using drugs to inhibit the AR actually results in stopping the repressive activity of the receptor. This leads to an increased level of SPINK1 gene expression.

The team established the role of SPINK1 gene for maintaining the characteristic features of NEPC. The tumor becomes aggressive when SPINK1 protein level increases while upon inhibiting the protein a decrease in the neuroendocrine markers was observed.

Along with androgen receptor, REST, which is a cofactor of AR, too was found to have repressive action on SPINK1 gene. The SPINK1 protein level was found to be high when the amount of REST is low as observed in prostate cancer, and in NEPC.

The team found that a particular protein named Casein Kinase 1 could potentially reduce the levels of REST. While inhibiting the protein using a standard drug was found to increase the levels of REST, shows the research.

The apparent increase in REST levels resulted in a decrease in SPINK1 protein level accompanied by a reduction in the oncogene properties of prostate cancer cells.

The researchers thus highlighted that treating prostate cancer cells showing elevated SPINK1 with a drug against Casein Kinase 1 shows reduced cancer cell growth as well as aggressiveness.

The authors emphasize on conducting clinical trials using casein kinase 1 inhibitor to investigate if the mechanism could reverse neuroendocrine prostate cancer and reduce SPINK1 in prostate cancer patients.

The study is published in the journal Nature Communications.