Paper Reading
01
Proteostasisby STUB1/HSP70 complex controls sensitivity to androgen receptor targetedtherapy in advanced prostate cancer
Chengfei Liu, Wei Lou, Joy C. Yang,Liangren Liu, Cameron M. Armstrong, Alan P. Lombard, Ruining Zhao, Onika D.V.Noel, Clifford G. Tepper, Hong-Wu Chen, Marc Dall’Era, Christopher P. Evans& Allen C. Gao.
NATURE COMMUNICATIONS ()
Protein homeostasis (proteostasis) is regulated through acomprehensive network, including molecular chaperone proteins, theubiquitin–proteasome system, and the autophagy system. Proteostasis is a potentialmechanism for controlling cancer cell survival and drug resistance. In advancedprostate cancer, sustained activation of androgen receptor (AR) variantsproduces anti-androgen resistance. However, the role of proteostasis in thenext generation of antiandrogen resistance and the mechanisms by which ARvariants are regulated remains poorly understood. Considerable evidencedemonstrates that truncated AR variants, particularly AR-V7, plays vital rolesin promoting CRPC progression during androgen deprivation therapy and in theinduction of resistance to enzalutamide and abiraterone therapy.
Recently, researchers have found that theubiquitin protease system (UPS) is inhibited inenzalutamide/abiraterone-resistant prostate cancer. The interaction of the E3ubiquitin ligase STUB1 and HSP70 complexes regulates AR/AR-V7 proteinproteostasis to regulates sensitivity to anti-androgens. STUB1 can separateAR/AR-V7 from HSP70, resulting in AR/AR-V7 ubiquitination and degradation.Inhibition of HSP70 can significantly inhibit the growth of prostate tumors byinhibiting AR/AR-V7, and can improve the therapeutic effect ofenzalutamide/abiraterone. Clinically, HSP70 expression is up-regulated inhigh-Gleason-score prostate tumors and is associated with AR/AR-V7 level.Finally, the researchers noted that their results elucidated a new mechanism ofanti-androgen resistance through UPS changes, which can reduce the expressionof AR-V7 by HSP70 inhibition.
/articles/s41467-018-07178-x
02
Linkingprostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses
Qiuhui Li, Qu Deng, Hsueh-Ping Chao, Xin Liu, Yue Lu, Kevin Lin,Bigang Liu, Gregory W. Tang, Dingxiao Zhang, Amanda Tracz, Collene Jeter, KieraRycaj, Tammy Calhoun-Davis, Jiaoti Huang, Mark A. Rubin, Himisha Beltran,Jianjun Shen, Gurkamal Chatta, Igor Puzanov, James L. Mohler, Jianmin Wang,Ruizhe Zhao, Jason Kirk, Xin Chen & Dean G. Tang.
NATURE COMMUNICATIONS ()
Human PCa is heterogeneous containing both AR-expressing (AR+), aswell as AR low- expressing or non-expressing (AR-/lo) cells and this ARheterogeneity is accentuated in expressing or non-expressing (AR/lo) cells andthis AR heterogeneity is accentuated in advanced metastatic and relapsed PCa.Whether the heterogeneity in AR expression levels
impacts PCa biology and therapy responseremains unclear.
Recently, researchers screened about 200 castrated resistant PCa(CRPC) lesions to explain the 3 modes of AR expression: nuclei (nuc-AR),nuclei/cytoplasm Mixed (nuc/cyto-AR) and low/no expression (AR-/lo). They foundthat AR-/lo CRPC is resistant to enzalutamide. Then they established AR+ andAR-knockout LNCaP cell clones and found different biological and tumorigenicproperties as well as different responses to enzalutamide. AR-KO LNCaP cellsresist enzalutamide in vitro and in vivo. RNA-Seq, biochemical analysis andexperimental combination therapy identified BCL-2 as a key therapeutic targetfor enzalutamide-resistant AR+/hi CRPC.
Finally, the researchers noted that their study linked the heterogeneity of AR expression to distinct tumorigenic behavior and castration/enzalutamideresponses. Critically, the paper uncovers signaling molecules and pathwaysunderlying the development of, and also establish proof-of-principletherapeutic regimens targeting, the two distinct castration resistance modesmediated by AR+/hi and AR-/lo PCa.
/articles/s41467-018-06067-7
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