Loss of Notch1 Activity Inhibits Prostate Cancer Growth and Metastasis and Sensitizes Prostate Cancer Cells to Antiandrogen Therapies

Abstract

Prostate cancer remains among the leading causes of cancerrelated deaths in men. Patients with aggressive disease typically undergo hormone deprivation therapy. Although treatment is initially very successful, these men commonly progress to lethal, castration-resistant prostate cancer (CRPC) in 2 to 3 years. Standard therapies for CRPC include second-generation antiandrogens, which prolong patient lifespan by only several months. It is imperative to advance our understanding of the mechanisms leading to resistance to identify new therapies for aggressive prostate cancer. This study identifies Notch1 as a therapeutic target in prostate cancer. Loss of NOTCH1 in aggressive prostate cancer cells decreases proliferation, invasion, and tumorsphere formation. Therapeutic inhibition of Notch1 activity with gamma secretase inhibitors RO4929097 or DAPT in prostate cancer cells further results in decreased proliferative abilities. Loss of NOTCH1 and treatment of immunocompromised mice bearing prostate cancer xenografts with RO4929097 display significantly impaired tumor growth. Loss of NOTCH1 additionally decreased metastatic potential of prostate cancer cells in invasion assays in vitro as well as in vivo experiments. Moreover, treatment with gamma secretase inhibitors or NOTCH1 gene deletion synergized with antiandrogen therapies, enzalutamide or abiraterone, to decrease the growth of prostate cancer cells. Combination of gamma secretase inhibitors with abiraterone significantly inhibited cell migration and invasion, while combination with enzalutamide reversed enzalutamide-induced migration and invasion. These collective findings suggest loss of NOTCH1 delays growth of CRPC and inhibits metastasis, and inhibition of Notch1 activation in conjunction with secondgeneration antiandrogen therapies could delay growth and progression of prostate cancer.

Upregulation of KLK8 Predicts Poor Prognosis in Pancreatic Cancer

“…These ndings suggest that elevated KLK8 may exert the pro-proliferation and anti-apoptotic effects in pancreatic cancer cells through activating PI3K-Akt-mTOR signaling pathway. Notch signaling pathway also plays an important role in the occurrence and progression of pancreatic cancer [40][41][42]. In the present study, GSEA analysis and western blot assay revealed that KLK8 overexpression resulted in the activation of Notch signaling pathway.…”

Second-Generation Antiandrogens: From Discovery to Standard of Care in Castration Resistant Prostate Cancer

“…MAOAI is also in clinical trial for non-metastatic PC clinical trials (NCT02217709). Finally, inhibitors of gamma secretase which regulates cleavage of cell surface receptors including Notch receptors among others, in combination with enzalutamide or abiraterone in vitro inhibits PC cell growth, migration and invasion, as well as sensitizes enzalutamide resistant cells and xenografts to enzalutamide treatment (116–119).…”

Top Notch Targeting Strategies in Cancer: A Detailed Overview of Recent Insights and Current Perspectives

“…Aside from breast cancer, lung cancer, ACC and possibly colorectal cancer, cell-autonomous activating Notch mutations in solid tumours are less common than haematological cancers. However, upregulation of wild-type Notch receptors and ligands, and aberrant Notch signalling is frequently observed in various tumours including melanoma [ 86 ], gastric cancer [ 87 ], ovarian cancer [ 88 ], prostate cancer [ 89 , 90 ], pancreatic cancer [ 91 , 92 ], hepatocellular carcinoma [ 93 , 94 , 95 ], glioma [ 40 , 96 , 97 ] and rare tumours such as cholangiocarcinoma [ 98 ] and desmoid tumours [ 99 ]. Notch gene alterations may play a role in a subset of these cancer cases; however, such mutations are yet to be identified.…”

“…Androgen deprivation therapy (ADT) with the use of AR antagonists such as enzalutamide is standardly used in the treatment of late-stage and metastatic prostate cancer and similar to ER antagonists, it is associated with a short response period and subsequent drug resistance [ 90 , 150 ]. A recent study has indicated that Notch 2 is overexpressed in enzalutamide-resistant prostate cancer patients, while cleaved or activated Notch 1 and HES-1 levels were increased in enzalutamide-resistant cell line models [ 219 ].…”

“…A recent study has indicated that Notch 2 is overexpressed in enzalutamide-resistant prostate cancer patients, while cleaved or activated Notch 1 and HES-1 levels were increased in enzalutamide-resistant cell line models [ 219 ]. Treatment of enzalutamide-resistant prostate cancer cells with the GSI, PF-03084014, or an alternative specific gene knockdown of Notch 1, resensitised cells to enzalutamide treatment, while the drug combination showed efficacy in xenograft models [ 90 ]. ADT has been shown to increase Notch 3 expression in prostate cancer cells while activation of any of the four NICDs increases resistance to ADT in androgen-dependent prostate cancer cells [ 150 ].…”