Development of new cancer therapy by regulating cytoskeleton and cancer-cell transformation

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The dynamics of the cytoskeleton including centrosomes-microtubules system is the basic mechanism for cancer -cell movement contributing to cancer invasion. We before proposed that developing the methods of regulating cytoskeleton in cancer cells might bring a strategy of cancer therapy. 1: In this project, we found that Hedgehog (HH) signaling pathway had changed its activity under the influence of paclitaxel, stabilizer of microtubules and attenuating the dynamics of cytoskeleton. 2: We also revealed that HH signaling was activated in breast, pancreatic and gastric cancers through immunostaining, real time RT-PCR and western-blotting of the surgically resected specimens or cancer cell lines. Shh, a ligand of the HH signal, is often up-regulated and leading its signal activation in cancer tissues and cell lines. Anti-Shh mAb as well as cyclopamine, a specific inhibitor of HH pathway, suppressed the signal in cancer cells, confirming the ligand-dependent activation of the HH signal in cancer. Interestingly, the activity of HH signaling was suppressed in colorectal cancers and up-regulation of HH signal suppressed the colorectal cancer-cell growth. This reverse effect of HH signaling pathway is consistent with its role in the development, survival effect in the foregut and inducing apoptosis in the hindgut. 3: When we suppressed the HH signal activity by cyclopamine in pancreatic cancer cells, their ability of invasion was attenuated in vitro as well as their growth. In contrast with cyclopamine, excess Shh activated their invasiveness. The mechanism by which Shh accelerate the pancreatic cancer invasion included up-regulation of their random movement controlled by cytoskeleton.