Sarah K. Martin

Elevated Stearoyl-CoA Desaturase in Brains of Patients with Alzheimer's Disease

The molecular bases of Alzheimers disease (AD) remain unclear. We used a lipidomic approach to identify lipid abnormalities in the brains of subjects with AD (N = 37) compared to age-matched controls (N = 17). The analyses revealed statistically detectable elevations in levels of non-esterified monounsaturated fatty acids (MUFAs) and mead acid (20:3n-9) in mid-frontal cortex, temporal cortex and hippocampus of AD patients. Further studies showed that brain mRNAs encoding for isoforms of the rate-limiting enzyme in MUFAs biosynthesis, stearoyl-CoA desaturase (SCD-1, SCD-5a and SCD-5b), were elevated in subjects with AD. The monounsaturated/saturated fatty acid ratio (‘desaturation index’) – displayed a strong negative correlation with measures of cognition: the Mini Mental State Examination test (r = −0.80; P = 0.0001) and the Boston Naming test (r = −0.57; P = 0.0071). Our results reveal a previously unrecognized role for the lipogenic enzyme SCD in AD.

Cofilin drives cell-invasive and metastatic responses to TGF-β in prostate cancer.

Cofilin (CFL) is an F-actin-severing protein required for the cytoskeleton reorganization and filopodia formation, which drives cell migration. CFL binding and severing of F-actin is controlled by Ser3 phosphorylation, but the contributions of this step to cell migration during invasion and metastasis of cancer cells are unclear. In this study, we addressed the question in prostate cancer cells, including the response to TGF-β, a critical regulator of migration. In cells expressing wild-type CFL, TGF-β treatment increased LIMK-2 activity and cofilin phosphorylation, decreasing filopodia formation. Conversely, constitutively active CFL (SerAla) promoted filipodia formation and cell migration mediated by TGF-β. Notably, in cocultures of prostate cancer epithelial cells and cancer-associated fibroblasts, active CFL promoted invasive migration in response to TGF-β in the microenvironment. Further, constitutively active CFL elevated the metastatic ability of prostate cancer cells in vivo. We found that levels of active CFL correlated with metastasis in a mouse model of prostate tumor and that in human prostate cancer, CFL expression was increased significantly in metastatic tumors. Our findings show that the actin-severing protein CFL coordinates responses to TGF-β that are needed for invasive cancer migration and metastasis.

N-terminal targeting of androgen receptor variant enhances response of castration resistant prostate cancer to taxane chemotherapy

Taxane‐based chemotherapy is an effective treatment for castration‐resistant‐prostate cancer (CRPC) via stabilization of microtubules. Previous studies identified that the inhibitory effect of microtubule‐targeting chemotherapy on androgen receptor (AR) activity was conferred by interfering with AR intracellular trafficking. The N‐terminal domain (NTD) of AR was identified as a tubulin‐interacting domain that can be effectively targeted by the novel small molecule inhibitor, EPI. Taken together this evidence provided the rationale that targeting AR nuclear translocation and activity via a combination of an antagonist of the AR NTD and taxane‐based chemotherapy may enhance the therapeutic response in CRPC. The present study investigated the anti‐tumor efficacy of a combination of EPI with Docetaxel chemotherapy, in cell models of CRPC, harboring the AR splice variants in addition to the full length AR. Our findings demonstrate that there was no significant effect on the androgen‐mediated nuclear transport of AR variants and AR transcriptional activity by Docetaxel. The therapeutic response to Docetaxel was enhanced by inhibition of the NTD of AR (by EPI) through cycling of epithelial‐mesenchymal‐transition (EMT) to mesenchymal‐epithelial‐transition (MET) among prostate cancer epithelial cells. These results support that transient “programming” of EMT by the AR NTD inhibitor, potentially drives the sensitivity of prostate tumors with differential distribution of AR variants to microtubule‐targeting chemotherapy. This study is of major significance in dissecting mechanisms to overcome taxane resistance in advanced CRPC.

Multinucleation and Mesenchymal-to-Epithelial Transition Alleviate Resistance to Combined Cabazitaxel and Antiandrogen Therapy in Advanced Prostate Cancer

Patients with metastatic castration-resistant prostate cancer (CRPC) frequently develop therapeutic resistance to taxane chemotherapy and antiandrogens. Cabazitaxel is a second-line taxane chemotherapeutic agent that provides additional survival benefits to patients with advanced disease. In this study, we sought to identify the mechanism of action of combined cabazitaxel and androgen receptor (AR) targeting in preclinical models of advanced prostate cancer. We found that cabazitaxel induced mitotic spindle collapse and multinucleation by targeting the microtubule depolymerizing kinesins and inhibiting AR. In androgen-responsive tumors, treatment with the AR inhibitor, enzalutamide, overcame resistance to cabazitaxel. Combination treatment of human CRPC xenografts with cabazitaxel and enzalutamide reversed epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) and led to multinucleation, while retaining nuclear AR. In a transgenic mouse model of androgen-responsive prostate cancer, cabazitaxel treatment induced MET, glandular redifferentiation, and AR nuclear localization that was inhibited by androgen deprivation. Collectively, our preclinical studies demonstrate that prostate tumor resistance to cabazitaxel can be overcome by antiandrogen-mediated EMT-MET cycling in androgen-sensitive tumors but not in CRPC. Moreover, AR splice variants may preclude patients with advanced disease from responding to cabazitaxel chemotherapy and antiandrogen combination therapy. This evidence enables a significant insight into therapeutic cross-resistance to taxane chemotherapy and androgen deprivation therapy in advanced prostate cancer.

Emerging biomarkers of prostate cancer (Review)

Prostate cancer progression involves activation of signaling pathways controlling cell proliferation, apoptosis, anoikis, angiogenesis and metastasis. The current PSA-based test for the diagnosis of prostate cancer lacks sensitivity and specificity, resulting in missed diagnoses and unnecessary biopsies. Intense research efforts to identify serum and tissue biomarkers will expand the opportunities to understand the functional activation of cancer-related pathways and consequently lead to molecular therapeutic targeting towards inhibition of tumor growth. Current literature describes multiple biomarkers that indicate the properties of prostate cancer including its presence, stage, metastatic potential and prognosis. Used singly, assays detecting these biomarkers have their respective shortcomings. Several recent studies evaluating the clinical utilization of multiple markers show promising results in improving prostate cancer profiling. This review discusses the current understanding of biomarker signature cluster-based approaches for the diagnosis and therapeutic response of prostate cancer derived from panels of biomarker tests that provide a selective molecular signature characteristic of the tumor. As these signatures are robustly defined and their pathways are exhaustively dissected, prostate cancer can be more accurately diagnosed, characterized, staged and targeted with inhibitory antitumor agents. The growing promise surrounding the recent evidence in identifying and utilizing such biomarker panels, will lead to improvement in cancer prognosis and management of the therapeutic response of prostate cancer patients.

Exploitation of the Androgen Receptor to Overcome Taxane Resistance in Advanced Prostate Cancer.

Prostate cancer is a tumor addicted to androgen receptor (AR) signaling, even in its castration resistant state, and recently developed antiandrogen therapies including Abiraterone acetate and enzalutamide effectively target the androgen signaling axis, but there is ultimately recurrence to lethal disease. Development of advanced castration-resistant prostate cancer (CRPC) is a biological consequence of lack of an apoptotic response of prostate tumor cells to androgen ablation. Taxanes represent the major clinically relevant chemotherapy for the treatment of patients with metastatic CRPC; unfortunately, they do not deliver a cure but an extension of overall survival. First-generation taxane chemotherapies, Docetaxel (Taxotere), effectively target the cytoskeleton by stabilizing the interaction of β-tubulin subunits of microtubules preventing depolymerization, inducing G2M arrest and apoptosis. Shifting the current paradigm is a growing evidence to indicate that Docetaxel can effectively target the AR signaling axis by blocking its nuclear translocation and transcriptional activity in androgen-sensitive and castration-resistant prostate cancer cells, implicating a new mechanism of cross-resistance between microtubule-targeting chemotherapy and antiandrogen therapies. More recently, Cabazitaxel has emerged as a second-line taxane chemotherapy capable of conferring additional survival benefit to patients with CRPC previously treated with Docetaxel or in combination with antiandrogens. Similar to Docetaxel, Cabazitaxel induces apoptosis and G2M arrest; in contrast to Docetaxel, it sustains AR nuclear accumulation although it reduces the overall AR levels and FOXO1 expression. Cabazitaxel treatment also leads to downregulation of the microtubule-depolymerizing mitotic kinesins, MCAK, and HSET, preventing their ability to depolymerize microtubules and thus enhancing sensitivity to taxane treatment. The molecular mechanisms underlying taxane resistance involve mutational alterations in the tubulin subunits, microtubule dynamics, phenotyping programming of the epithelial-to-mesenchymal transition landscape, and the status of AR activity. This chapter discusses the mechanisms driving the therapeutic resistance of taxanes and antiandrogen therapies in CRPC, and the role of AR in potential interventions toward overcoming such resistance in patients with advanced metastatic disease.

Gene fusions find an ERG-way to tumor inflammation

Commentary to: ERG oncogene modulates prostaglandin signaling in prostate cancer cells Ahmed A. Mohamed, Shyh-Han Tan, Chen Sun, Syed Shaheduzzaman, Ying Hu, Gyorgy Petrovics, Yongmei Chen, Isabell A. Sesterhenn, Hua Li, Taduru Sreenath, David G. McLeod, Albert Dobi and Shiv Srivastava

Androgen Receptor Signaling Interactions Control Epithelial–Mesenchymal Transition (EMT) in Prostate Cancer Progression

The role of the androgen receptor (AR) signaling axis in the progression of prostate cancer is a cornerstone to our understanding of the molecular mechanisms behind this important disease. Understanding the innate signaling axis of the AR and the aberrations of this axis in progression of prostate cancer has facilitated the development of emerging therapeutic interventions. Furthermore, the crosstalk of AR with other critical signaling pathways may explain the advancement of prostate cancer to metastatic castration-resistant prostate cancer (CRPC). Of particular interest to such crosstalk are the pathways associated with epithelial to mesenchymal transition (EMT). The reactivation of EMT is a hallmark of metastatic cancer spread, and recent evidence suggests the involvement of AR in the signaling pathways regulating EMT. Cadherin switching, EMT inducing transcription factors, Wnt, TGF-β, and Notch signaling can all be modulated by crosstalk with the AR. Overexpression and localization of the AR to the nucleus has been associated with reactivation of the androgenic signaling axis and progression to metastatic CRPC in patients. In this chapter we consider the current understanding of the functional exchanges between the androgen signaling championed by AR activity and key growth factor signaling pathways that impact EMT towards prostate cancer progression to metastatic CRPC and we discuss the clinical relevance of these insights in the effective targeting of advanced disease.

Abstract 2567: Cabazitaxel chemotherapy targets mitotic kinesins resulting in multi-nucleation of prostate cancer cells: A novel mechanism of cross-resistance with antiandrogens in advanced CRPC

Progression to castration-resistant prostate cancer (CRPC) is characterized by increased androgen receptor (AR) and activated AR signaling despite castrate levels of androgens. The FDA-approved next generation microtubule stabilizing taxane, Cabazitaxel (CBZ) and novel anti-androgen Enzalutamide (MDV) have demonstrated additional survival benefits for patients with advanced CRPC. The present study pursued the mechanism of therapeutic resistance to CBZ and antiandrogen treatment in models of CRPC. The effect CBZ and/or MDV was examined in human prostate cancer cells: androgen independent (DU145 and PC3), androgen responsive (LNCaP and VCaP) and CRPC (22Rv1 and PC3-ARv567, harboring AR variants). Cell viability assessment revealed that CRPC PC3-ARv567es and the androgen-sensitive VCaP cells exhibited resistance to CBZ; however the 22Rv1 cells responded to CBZ and MDV combination with a significant increase in growth (P