Cancer cells frequently use fructose as an alternative energy and carbon source, to fuel glycolysis and support the synthesis of various biomacromolecules. Glut5 is the only fructose-specific transporter, which lacks the ability to transport other carbohydrates such as glucose and galactose. Interplay between inflammatory factors and cancer cells renders inflammatory tissue environment as a predisposing condition for cancer development. Nevertheless, how inflammatory factors coordinate with fructose metabolism to facilitate tumor growth remains largely elusive. Here we show that treatment with IL-6 activates fructose uptake and fructolysis in oral squamous cell carcinoma (OSCC) cells and prostate cancer cells. Mechanistic study shows that transcription factor STAT3 associates with Glut5 promoter region and enhances Glut5 transcription in response to IL-6 treatment. Knockdown of Glut5 abolished IL-6-induced fructose uptake and utilization of fructose, and compromises IL-6-elicited tumor cell proliferation. Further, positive correlation between Glut5 and IL-6 expression is observed in multiple cancers. Our findings demonstrate a regulatory cascade underlying the crosstalk between inflammation and fructose metabolism in cancer cells, and highlights Glut5 as a novel oncogenic factor.

Prostate cancer ranks among the most commonly diagnosed malignancies for men and has become a non‐negligible threat for public health. Interplay between inflammatory factors and cancer cells renders inflammatory tissue environment as a predisposing condition for cancer development. The Hippo pathway is a conserved signaling pathway across multiple species during evolution that regulates tissue homeostasis and organ development. Nevertheless, whether Hippo pathway regulates cancer‐related inflammatory factors remains elusive. Here, we show that high cell density–mediated activation of the Hippo pathway blunts STAT3 activity in prostate cancer cells. Hippo pathway component MST2 kinase phosphorylates STAT3 at T622, which is located in the SH2 domain of STAT3. This phosphorylation blocks the SH2 domain in one STAT3 molecule to bind with the phosphorylated Y705 site in another STAT3 molecule, which further counteracts IL6‐induced STAT3 dimerization and activation. Expression of a nonphosphorylatable STAT3 T622A mutant enhances STAT3 activity and IL6 expression at high cell density and promotes tumor growth in a mice xenograft model. Our findings demonstrate that STAT3 is a novel phosphorylation substrate for MST2 and thereby highlight a regulatory cascade underlying the crosstalk between inflammation and the Hippo pathway in prostate cancer cells.

IntroductionLong non-coding RNA Membrane-Associated Guanylate Kinase Inverted 2 Antisense RNA 3 (MAGI2-AS3) has been identified as a predictive characteristic for prostate cancer (PC). However, the underlying mechanism of MAGI2-AS3 in PC is yet unclear.Material and methodsThe gene expression was detected via reverse transcription quantitative PCR. Cell viability, apoptosis and invasion were detected via cell counting kit-8, caspase-3 activity, flow cytometry, and transwell assays. Tumor xenograft experiment was performed to measure the tumor growth in vivo. Luciferase and radioimmunoprecipitation assays were utilized to determine the association between microRNA (miR)-142-3p and MAGI2-AS3 or proline-rich membrane anchor 1 (PRIMA1).ResultsMAGI2-AS3 and PRIMA1 were established to be downregulated in PC, whereas miR-142-3p exhibited the upregulation in PC. In vitro and in vivo loss-of-function assays demonstrated that MAGI2-AS3 silencing increased the viability and invasiveness, enhanced the tumor growth of PC cells, while reducing apoptosis. PRIMA1 silencing in PC cells showed the similar effect as MAGI2-AS3 silencing. Moreover, the miR-142-3p inhibitor reversed the impacts of the downregulation of MAGI2-AS3 or PRIMA1 on the malignant behavior of PC cells.ConclusionsMAGI2-AS3 knockdown enhanced the malignant behavior of PC cells by targeting miR-142-3p to suppress PRIMA1 expression. Our findings reveal that MAGI2-AS3 can be a promising therapeutic target for the treatment of PC.