Castration-Resistant Prostate Cancer: Mechanisms, Targets, and Treatment

Amaral, Teresa; Macedo, Daniela; Fernandes, Isabel; Costa, Luís

doi:10.1155/2012/327253

Cited by 91 publications

(87 citation statements)

References 89 publications

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“…rostate cancer is the most common malignancy and the second leading cause of cancer-related mortality among men in the United States (1). Although androgen deprivation therapy (through medical or surgical castration) is highly effective for advanced prostate cancer (1,2), the majority of patients eventually develop resistance and progress to castration-resistant prostate cancer (CRPC).…”

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confidence: 99%

“…Although androgen deprivation therapy (through medical or surgical castration) is highly effective for advanced prostate cancer (1,2), the majority of patients eventually develop resistance and progress to castration-resistant prostate cancer (CRPC). Unfortunately, most cases of CRPC are currently incurable (1). The cause of castration resistance is still not completely known.…”

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confidence: 99%

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The Hippo Pathway Effector YAP Regulates Motility, Invasion, and Castration-Resistant Growth of Prostate Cancer Cells

Zhang¹,

Yang²,

Chen³

et al. 2015

Molecular and Cellular Biology

142

151

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f Yes-associated protein (YAP) is an effector of the Hippo tumor suppressor pathway. The functional significance of YAP in prostate cancer has remained elusive. In this study, we first show that enhanced expression of YAP is able to transform immortalized prostate epithelial cells and promote migration and invasion in both immortalized and cancerous prostate cells. We found that YAP mRNA was upregulated in androgen-insensitive prostate cancer cells (LNCaP-C81 and LNCaP-C4-2 cells) compared to the level in androgen-sensitive LNCaP cells. Importantly, ectopic expression of YAP activated androgen receptor signaling and was sufficient to promote LNCaP cells from an androgen-sensitive state to an androgen-insensitive state in vitro, and YAP conferred castration resistance in vivo. Accordingly, YAP knockdown greatly reduced the rates of migration and invasion of LNCaP-C4-2 cells and under androgen deprivation conditions largely blocked cell division in LNCaP-C4-2 cells. Mechanistically, we found that extracellular signal-regulated kinase-ribosomal s6 kinase signaling was downstream of YAP for cell survival, migration, and invasion in androgen-insensitive cells. Finally, immunohistochemistry showed significant upregulation and hyperactivation of YAP in castration-resistant prostate tumors compared to their levels in hormone-responsive prostate tumors. Together, our results identify YAP to be a novel regulator in prostate cancer cell motility, invasion, and castration-resistant growth and as a potential therapeutic target for metastatic castration-resistant prostate cancer (CRPC). P rostate cancer is the most common malignancy and the second leading cause of cancer-related mortality among men in the United States (1). Although androgen deprivation therapy (through medical or surgical castration) is highly effective for advanced prostate cancer (1, 2), the majority of patients eventually develop resistance and progress to castration-resistant prostate cancer (CRPC). Unfortunately, most cases of CRPC are currently incurable (1). The cause of castration resistance is still not completely known. It is expected that understanding the molecular mechanisms and identifying the molecular pathways underlying the acquisition of castration resistance in prostate cancer are critical for the design of therapeutic strategies and may lead to the discovery of novel targets.The Hippo signaling pathway, originally defined by fly geneticists, plays an important role in tumorigenesis by regulating cell proliferation and apoptosis (3-7). In mammals, protein kinases Mst1/2 (mammalian sterile 20-like 1 and 2) and Lats1/2 (large tumor suppressor 1 and 2) and the adaptor proteins WW45 (WW domain-containing protein) and Mob1 (Mps one binder 1) are the Hippo core components. These proteins form complexes to regulate their activity mainly through phosphorylation. The Hippo core is tumor suppressive and exerts its function by phosphorylating and inactivating YAP (Yes-associated protein) and its paralog, TAZ (transcriptional coactivator with a PDZ-bi...

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confidence: 99%

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confidence: 99%

The Hippo Pathway Effector YAP Regulates Motility, Invasion, and Castration-Resistant Growth of Prostate Cancer Cells

Zhang¹,

Yang²,

Chen³

et al. 2015

Molecular and Cellular Biology

142

151

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“…In about 30% of cases, however, the tumor relapses in 5-10 years, often at metastatic sites. Since prostate cancer is in most cases initially androgen sensitive, for these patients and for patients with a disseminated disease at the time of diagnosis, androgen deprivation by surgical or chemical castration is the treatment of choice (Amaral et al 2012). Androgen deprivation can be achieved surgically, by orchiectomy, or chemically by targeting the androgen receptor (AR) pathway, either desensitizing it with luteinizing hormone-releasing hormone (LHRH) agonists or blocking it by LHRH antagonists or by antagonists of the AR (Pham et al 2016).…”

Section: Amcd Use In Prostate Cancer Therapymentioning

confidence: 99%

Fighting tubulin-targeting anticancer drug toxicity and resistance

Visconti

Grieco

2017

Endocrine-Related Cancer

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Tubulin-targeting drugs, like taxanes and vinca alkaloids, are among the most effective anticancer therapeutics used in the clinic today. Specifically, anti-microtubule cancer drugs (AMCDs) have proven to be effective in the treatment of castration-resistant prostate cancer and triple-negative breast cancer. AMCDs, however, have limiting toxicities that include neutropenia and neurotoxicity, and, in addition, tumor cells can become resistant to the drugs after long-term use. Co-targeting mitotic progression/ slippage with inhibition of the protein kinases WEE1 and MYT1 that regulate CDK1 kinase activity may improve AMCD efficacy, reducing the acquisition of resistance by the tumor and side effects from the drug and/or its vehicle. Other possible treatments that improve outcomes in the clinic for these two drug-resistant cancers, including new formulations of the AMCDs and pursuing different molecular targets, will be discussed.

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“…12 Unfortunately, progression of prostate cancer cells to a more aggressive and metastatic phenotype is possible through a number of pathways, including the androgen-independent activation of the AR through gene amplification and mutation as well as intratumoral synthesis of testosterone. 12,13 This constitutes castration-resistant prostate cancer (CRPC), which often displays simultaneous metastatic capabilities with a propensity for the bone microenvironment causing much morbidity. 14 At this stage, therapeutic options are limited and the disease has become incurable.…”

Section: Prostate Cancer and Oxidative Stress Prostate Cancer-a Briefmentioning

confidence: 99%