MAPK4 promotes prostate cancer by concerted activation of androgen receptor and AKT
Tao Shen, Wei Wang, Wolong Zhou, Ilsa Coleman, Qinbo Cai, Bingning Dong, Michael M. Ittmann, Chad J. Creighton, Yingnan Bian, Yanling Meng, David R. Rowley, Peter S. Nelson, David D. Moore, Feng Yang
Tao Shen, Wei Wang, Wolong Zhou, Ilsa Coleman, Qinbo Cai, Bingning Dong, Michael M. Ittmann, Chad J. Creighton, Yingnan Bian, Yanling Meng, David R. Rowley, Peter S. Nelson, David D. Moore, Feng Yang
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Research Article Oncology

MAPK4 promotes prostate cancer by concerted activation of androgen receptor and AKT

Abstract

Prostate cancer (PCa) is the second leading cause of cancer death in American men. Androgen receptor (AR) signaling is essential for PCa cell growth/survival and remains a key therapeutic target for lethal castration-resistant PCa (CRPC). GATA2 is a pioneer transcription factor crucial for inducing AR expression/activation. We recently reported that MAPK4, an atypical MAPK, promotes tumor progression via noncanonical activation of AKT. Here, we demonstrated that MAPK4 activated AR by enhancing GATA2 transcriptional expression and stabilizing GATA2 protein through repression of GATA2 ubiquitination/degradation. MAPK4 expression correlated with AR activation in human CRPC. Concerted activation of both GATA2/AR and AKT by MAPK4 promoted PCa cell proliferation, anchorage-independent growth, xenograft growth, and castration resistance. Conversely, knockdown of MAPK4 decreased activation of both AR and AKT and inhibited PCa cell and xenograft growth, including castration-resistant growth. Both GATA2/AR and AKT activation were necessary for MAPK4 tumor-promoting activity. Interestingly, combined overexpression of GATA2 plus a constitutively activated AKT was sufficient to drive PCa growth and castration resistance, shedding light on an alternative, MAPK4-independent tumor-promoting pathway in human PCa. We concluded that MAPK4 promotes PCa growth and castration resistance by cooperating parallel pathways of activating GATA2/AR and AKT and that MAPK4 is a novel therapeutic target in PCa, especially CRPC.

Authors

Tao Shen, Wei Wang, Wolong Zhou, Ilsa Coleman, Qinbo Cai, Bingning Dong, Michael M. Ittmann, Chad J. Creighton, Yingnan Bian, Yanling Meng, David R. Rowley, Peter S. Nelson, David D. Moore, Feng Yang

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Figure 8

MAPK4 promotes prostate tumor growth and its expression correlates with AR activation in human CRPC.

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MAPK4 promotes prostate tumor growth and its expression correlates with ...
Dox-induced overexpression of MAPK4 promotes LNCaP xenograft growth in (A) intact SCID mice and (B) castrated SCID mice. (C) Dox-induced knockdown of MAPK4 inhibits LAPC4 xenograft growth in SCID mice. 2 × 106 of LNCaP-iMAPK4, LNCaP-iCtrl, LAPC4-iNT, or LAPC4-ishMAPK4 cells were injected into the lateral flanks (SubQ) of intact or castrated SCID mice (iCtrl or iNT on the left side; iMAPK4 or ishMAPK4 on the right side). Mice began receiving Dox (0.2 mg/mL for LNCaP and 4 mg/mL for LAPC4 xenografts) in 10% sucrose in drinking water on the day of xenograft implantation. Tumors were harvested as indicated. (D) Dox-induced knockdown of MAPK4 inhibits the growth of previously established 22Rv1 xenograft tumors in castrated SCID mice. A quantity of 2 × 106 22Rv1-iNT or 22Rv1-ishMAPK4 cells were injected into the lateral flanks (SubQ) of castrated SCID mice (iNT on the left side; ishMAPK4 on the right side). Mice began receiving Dox (4 mg/ml) in 10% sucrose in drinking water when tumors grow into about 100 mm3. Tumors were harvested as indicated. iMAPK4 and iCtrl: Dox-inducible expression of MAPK4 or control. ishMAPK4 and iNT: Dox-inducible knockdown of MAPK4 or nontargeting control. Data represent mean ± SEM. P values determined by unpaired 2-tailed Student’s t test. *P ≤ 0.05. **P ≤ 0.01. ***P ≤ 0.001. Data are representative of at least 3 independent experiments. (E) Western blots on an independent set of LAPC4-iNT or LAPC4-ishMAPK4 tumors (a repeated study of panel C). Data are representative of at least 3 independent experiments. (F) MAPK4 mRNA expression correlates with AR activation status in human CRPC tissues.