Activity of ROCKII not ROCKI promotes pulmonary metastasis of melanoma cells via modulating Smad2/3-MMP9 and FAK-Src-VEGF signalling

• Published in: Cellular signalling Vol. 97; p. 110389
• Main Authors: Chatterjee, Sujan, Patra, Debajyoti, Ghosh, Pujita, Banerjee, Soumi, Chowdhury, Kaustav Dutta, Chakraborty, Pratip, Basu, Anupam, Sadhukhan, Gobinda Chandra
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.09.2022
• Subjects: KD-025; Metastatic lung melanoma; MMP9; pROCKIISer1366; Smad complex; VEGF regulatory axis; PBS; IL; ROCK; VEGF regulatory axis; DMSO; JNK; VEGF; pROCKIISer1366; CDK; HMGB1; EDTA; MMP9; ECM; CBP; KD-025; DMEM; FAK; MMP; STAT; Metastatic lung melanoma; FBS; TGFβ; Smad complex; Smad
• ISSN: 0898-6568; 1873-3913; 1873-3913
• DOI: 10.1016/j.cellsig.2022.110389

Rho-associated coiled-coil kinase (ROCK) inhibition decreases tumourogenic growth, proliferation and angiogenesis. Multifaceted evidences are there about the role of ROCK in cancer progression, but isoform specific analysis in secondary pulmonary melanoma is still unaddressed. This study explored the operating function of ROCK in the metastasis of B16F10 mice melanoma cell line. Inhibition by KD-025 indicated dual wielding role of ROCKII as it is associated with the regulation of MMP9 activity responsible for extra-cellular matrix (ECM) degradation as well as angiogenic invasion as an effect of Src-FAK-STAT3 interaction dependent VEGF switching. We found the assisting role of ROCKII, not ROCKI in nuclear localization of Smads that effectively increased MMP9 expression and activity (p < 0.01). This cleaved the protein components of ECM thereby played a crucial role in tissue remodeling at secondary site during establishment of metastatic tumour. ROCKII phosphorylation at Ser1366 as an activation of the same was imprinted essential for oncogenic molecular bagatelle leading to histo-architectural change of pulmonary tissue with extracellular matrix degradation as a consequence of invasion. Direct correlation of pROCKIISer1366 with MMP9 as well as VEGF expression in vivo studies cue to demonstrate the importance of pROCKIISer1366 inhibition in the context of angiogenesis, and metastasis suggesting ROCKII signaling as a possible target for the treatment of secondary lung cancer specially in metastatic melanoma. [Display omitted] •Chief operating role of ROCKII in Src-FAK-STAT3 complex mediated VEGF expression.•ROCKII activation regulates nuclear localization of Smad complex and MMP9 activity.•The p-ROCKII-Ser1366, the active ROCKII is key player for secondary lung melanoma.•KD-025 restricts ECM degradation and angiogenesis in metastatic lung melanoma.