Τίτλος:
Androgen Receptor Signaling in Castration-Resistant Prostate Cancer Alters Hyperpolarized Pyruvate to Lactate Conversion and Lactate Levels In Vivo
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Purpose: Androgen receptor (AR) signaling affects prostate cancer (PCa) growth, metabolism, and progression. Often, PCa progresses from androgen-sensitive to castration-resistant prostate cancer (CRPC) following androgen-deprivation therapy. Clinicopathologic and genomic characterizations of CRPC tumors lead to subdividing CRPC into two subtypes: (1) AR-dependent CRPC containing dysregulation of AR signaling alterations in AR such as amplification, point mutations, and/or generation of splice variants in the AR gene; and (2) an aggressive variant PCa (AVPC) subtype that is phenotypically similar to small cell prostate cancer and is defined by chemotherapy sensitivity, gain of neuroendocrine or pro-neural marker expression, loss of AR expression, and combined alterations of PTEN, TP53, and RB1 tumor suppressors. Previously, we reported patient-derived xenograft (PDX) animal models that contain characteristics of these CRPC subtypes. In this study, we have employed the PDX models to test metabolic alterations in the CRPC subtypes. Procedures: Mass spectrometry and nuclear magnetic resonance analysis along with in vivo hyperpolarized 1-[ 13 C]pyruvate spectroscopy experiments were performed on prostate PDX animal models. Results: Using hyperpolarized 1-[ 13 C]pyruvate conversion to 1-[ 13 C]lactate in vivo as well as lactate measurements ex vivo, we have found increased lactate production in AR-dependent CRPC PDX models even under low-hormone levels (castrated mouse) compared to AR-negative AVPC PDX models. Conclusions: Our analysis underscores the potential of hyperpolarized metabolic imaging in determining the underlying biology and in vivo phenotyping of CRPC. © 2018, World Molecular Imaging Society.
Συγγραφείς:
Zacharias, N.
Lee, J.
Ramachandran, S.
Shanmugavelandy, S.
McHenry, J.
Dutta, P.
Millward, S.
Gammon, S.
Efstathiou, E.
Troncoso, P.
Frigo, D.E.
Piwnica-Worms, D.
Logothetis, C.J.
Maity, S.N.
Titus, M.A.
Bhattacharya, P.
Περιοδικό:
Molecular Imaging and Biology
Εκδότης:
Springer New York LLC
Λέξεις-κλειδιά:
alanine; androgen receptor; carbon 13; epitestosterone; lactate dehydrogenase; lactic acid; pyruvic acid; succinic acid, androgen deprivation therapy; animal experiment; animal model; animal tissue; Article; castration resistant prostate cancer; ex vivo study; gene expression; genetic variability; hormone determination; in vivo study; male; mass spectrometry; mouse; nonhuman; nuclear magnetic resonance; patient derived xenograft; phenotype; point mutation; priority journal; signal transduction; tumor xenograft
DOI:
10.1007/s11307-018-1199-6
