Consistently, the colon cancer cells has been found to utilize similar pathway as myoblasts through which MEK inhibition activates Mirk/Dyrk1B promoter constructs and increases Mirk/Dyrk1B tran scription. In this MLN2238 study, we also found Mirk/Dyrk1B could be up regulated by serum depleted culture or U0126 treatment in both ovarian cancer and NSCLC cells. Therefore, Our study along with others sug gests that MAPK/ERK signaling may inhibit Mirk/ Dyrk1B transcription and functions in human cancer cells. In addition, our results in the study demonstrate that the widely expressed Mirk/Dyrk1B in both ovarian cancer and NSCLC cells largely correlates the activated ERK1/2. Moreover, we have also found Mirk/Dyrk1B protein levels were increased by inhibition of MEK ERK1/2, and knockdown of Mirk/Dyrk1B resulted in up regulation of activated ERK1/2 as well as up/down stream signals.

All together indicate the possible inter action between Mirk/Dyrk1B and MAPK/ERK signals in human cancer cells. Namely, Mirk/Dyrk1B may seques ter MAPK/ERK, and vice versa in either myogenesis or cancer. In the past decade, growing evidence has demon strated that knockdown Mirk/Dyrk1B could induce cell apoptosis and increase sensitivity of various human can cer cells to conventional chemotherapeutics. Further more, the study in osteosarcoma demonstrates that the overall survival rate of patients is negatively correlated with the levels of Mirk/Dyrk1B protein expression. Our previous studies have also shown Mirk/Dyrk1B function in an NSCLC orthotopic mouse model, and the involvement of FoxO1/3A in the Mirk mediated ovarian cancer cell survival.

Recently, studies have focused on the effect of Mirk/Dyrk1B on various human cancer cells arrested in a reversible quiescent state to undergo DNA repair or survive suboptimal growth conditions. Moreover, Mirk/Dyrk1B, through regulating cyclin D turnover and p27 stabilization, functions independently and additively to regulate the exit of cancer cells from quiescence G0 or early G1 into S and G2/M of cell cycle. Although it has been reported that Mirk could be negatively regulated by MAPK/ERK in colon cancer, our study is the first to show the possible interaction between Mirk/Dyrk1B and MAPK/ERK signals or sequestering with each other in both ovarian cancer and NSCLC cells.

In this study, Carfilzomib knockdown of Mirk/Dyrk1B by siRNA in either ovarian cancer cells or NSCLC cells led to up regulated activation of c Raf MEK ERK1/2 pathway, ac companied by increased growth rate and cells from G0/G1 into S of cell cycle which could be blocked by U0126 in a dose dependent manner. Furthermore, combined Mirk siRNA and U0126 induced cell apoptosis in the human cancer cells. All of above suggest that Mirk/Dyrk1B may mediate cell cycle and cell survival through interacting with MAPK/ERK pathway in human cancer.