STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway

Pencik, J; Philippe, C; Schlederer, M; Atas, E; Pecoraro, M; Grund-Gröschke, S; Li, WJ; Tracz, A; Heidegger, I; Lagger, S; Trachtová, K; Oberhuber, M; Heitzer, E; Aksoy, O; Neubauer, HA; Wingelhofer, B; Orlova, A; Witzeneder, N; Dillinger, T; Redl, E; Greiner, G; D’Andrea, D; Östman, JR; Tangermann, S; Hermanova, I; Parkes, EE

Journal article

STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway

Abstract:: Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa.

Publication status:: Published

Peer review status:: Peer reviewed

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APA Style

Pencik, J., Philippe, C., Schlederer, M., Atas, E., Pecoraro, M., Grund-Gröschke, S., Li, W. J., Tracz, A., Heidegger, I., Lagger, S., Trachtová, K., Oberhuber, M., Heitzer, E., Aksoy, O., Neubauer, H. A., Wingelhofer, B., Orlova, A., Witzeneder, N., Dillinger, T., … Parkes, E. E. (2023). STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway. Molecular Cancer, 22(1), 133–133.

MLA Style

Pencik, J, et al. “STAT3/LKB1 Controls Metastatic Prostate Cancer by Regulating mTORC1/CREB Pathway.” Molecular Cancer, vol. 22, no. 1, 2023, pp. 133–33.

Chicago Style

Pencik, J, C Philippe, M Schlederer, et al. 2023. “STAT3/LKB1 Controls Metastatic Prostate Cancer by Regulating mTORC1/CREB Pathway.” Molecular Cancer 22 (1): 133–33.
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