The Role of PIM Kinases in Prostate Cancer: Promoting and Inhibiting Factors

Prostate cancer is the most common cancer in males, and it is one of the leading causes of death in developed countries. Although, the five-year life expectancy of all diagnosed cases is usually good, prostate cancer is still a fatal disease. Prostate cancer is often diagnosed based on elevated prostate specific antigen (PSA) values, digital rectal examinations (DRE), and needle biopsies of the prostate. The most common therapy options for prostate cancer are surgery or radiation therapy, androgen deprivation therapy (ADT), and chemotherapy. As altered androgen receptor (AR) signaling is central in the development and progression of prostate cancer, ADT as primary therapy is initially functional. However, eventually cancer develops to a castration-resistant form for which there is no curative treatment available. In prostate cancer, formation of metastases to distant organs, especially to adjacent lymph nodes and bones is an unfavorable and difficult characteristic in terms of functional therapy options (Teo et al. 2019).

PIM kinases are well-known oncoproteins promoting cell proliferation, migration, and survival as well as stimulating activities of several transcription factors that can contribute to tumorigenesis. PIM kinases form a family of serine/threonine kinases that consists of three members, PIM1, PIM2, and PIM3. The functions and expression patterns of these three family members are partially overlapping. Enhanced expression of PIM family members has been detected both in hematopoietic malignancies and in solid tumors such as prostate cancer, where PIM overexpression has been shown to correlate with tumor aggressiveness and thereby also with worse prognosis of patients. In this thesis, the expression levels of different PIM family members were studied during prostate cancer progression, and prostate cancer cell lines and xenograft models were used to evaluate the effects of PIM inhibition on tumor growth and metastatic motility. We demonstrated that higher expression levels of PIM kinases increase tumor growth and cancer cell motility and thereby enhance the formation of metastases. By contrast, inhibition of PIM kinases by specific PIM-selective inhibitors decreased tumor growth and metastatic potential of prostate cancer. In prostate cancer patient samples, expression of all PIM kinases was increased compared to benign prostate samples. Moreover, PIM1 and PIM2 protein levels were further increased during prostate cancer development from hormone-naïve primary tumor into castration-resistant prostate cancer.

The NFATC1 transcription factor is one of the PIM1 kinase substrates whose transactivation potential is enhanced by PIM1-dependent phosphorylation. In the immune system, NFATC transcription factors transcriptionally regulate the activation, development, and differentiation of helper T-cells. In addition, upregulated activities of both PIM and NFATC1 have been shown to promote tumorigenesis by regulating cell proliferation, migration, invasion, and angiogenesis. In this thesis, PIM kinases have been demonstrated to enhance NFATC1 activity through phosphorylation of seven serine and three threonine residues, leading to increased migration and invasion of prostate cancer cells. Additionally, we have identified alpha 5 integrin (ITGA5) as a potent target of the interplay between PIM and NFATC1 in prostate cancer, where it increases invasion of cancer cells.

To exert their oncogenic functions in cancer cells, PIM kinases co-operate with other tumorigenic proteins. In prostate cancer, these proteins include the MYC and ERG transcription factors which are commonly overexpressed there. Here, we examined co-expression of all PIM kinases with these oncoproteins and evaluated how they regulate PIM-dependent signaling. Our data suggests that both PIM1 and PIM3 cooperate with MYC in prostate tumorigenesis. Moreover, our results indicate that ERG associates with and regulates the expression of all three PIM kinases in prostate cancer cells.

Altogether, results presented in this thesis indicate that PIM kinases have an important role in the development and progression of prostate cancer. Moreover, inhibition of the PIM signaling pathway may provide benefits especially for such patients who have high PIM expression levels and metastatic cancer. As PIM kinases co-operate with several other oncoproteins, their targeted inhibition in combinations may be more profitable than monotherapies. However, additional studies will be needed to evaluate the efficacy of such combinatorial therapies.