STAT3 restricts prostate cancer metastasis and antiandrogen resistance by controlling LKB1/CREB signaling pathway

Abstract

Prostate cancer (PCa) lethality is driven by its progression to a metastatic castration-resistant state, yet the signaling mechanisms underlying metastatic spread remain unknown. Here we show that STAT3 converges with the LKB1/mTORC1 and CREB to control metastatic disease in PCa mouse models. Unexpectedly, STAT3 was found to be upregulated in diabetic PCa patients undergoing metformin therapy with a concomitant reduction in mTORC1 expression. In preclinical mouse models of PCa, genetic ablation or activation of STAT3 had opposing effects on LKB1/AMPK/mTORC1-dependent tumorigenesis. Using genetic and pharmacological approaches, we identified LKB1 as a direct STAT3 target while repressing CREB. Furthermore, PCa patients with high CREB expression had inferior clinical outcome with significantly increased risk of disease and metastatic recurrence. We observe that castration state lowers STAT3 abundance and increases AR and CREB levels, leading to castration-resistant PCa (CRPC). Our findings revealed that STAT3 controls mTORC1 and CREB in metastatic disease, suggesting CREB as a promising target for lethal CRPC.

JUN mediates senescence and immune cell recruitment to prevent prostate cancer progression

“…Comparable to the human situation, Pten loss leads to the formation of precancerous lesions in PE cells in mouse models [52,53]. Aggressive carcinomas develop only in the presence of additional mutations [54], such as abnormal expression of ERG [55], loss of IL-6/STAT3 functionality [12,13], dysfunction of the methyltransferase Kmt2c [28] or activation of the RAS/MAPK cascade [54,56]. While several studies indicate that augmented JUN expression drives PCa progression [14,57], the functional role of JUN and AP-1 TFs in PCa remains controversial.…”

“…Our recent investigations have shown the potential of the antidiabetic agent metformin, which curtails multiple pro-inflammatory SASP components by inhibiting NF-κB nuclear translocation [73]. Metformin increases STAT3 in advanced PCa cases, leading to significant tumor growth attenuation, underscored by reduced mTORC1/CREB and AR levels in a PCa murine model [13]. The interplay between JUN and STAT3 might represent a key mechanism that could be exploited for therapeutic advances.…”

“…IL-6 and its downstream effector signal transducer and activator of transcription 3 (STAT3) are known to regulate apoptosis, angiogenesis, proliferation and differentiation, making them promising therapeutic targets in PCa [11]. However, our group has recently challenged active IL-6/STAT3 signaling as a tumor driver in PCa, as loss of Stat3 unexpectedly resulted in increased tumor burden and was accompanied by a bypass of Pten-loss induced cellular senescence (PICS) in a Pten-deficient PCa mouse model [12,13].…”