mct2 pathway p and p which are downstream of pAkt
p21 and p16, which are downstream of pAkt and pERK1/2, are tumor suppressors which induce cell senescence and mct2 pathway arrest [, , ]. Inhibitors of pAkt or pERK1/2 can activate p21 and p16 and promote cell senescence and cell cycle arrest [11,12,, , ]. It is well known that p21 is closely related to both G0/1 and G2/M phase arrest [62,63]. However, in our study, NCTD induced G2/M phase arrest and signaling inhibitors induced G0/1 arrest in TNBC. This inconsistency may be explained by NCTD, but not the inhibitors, causing DNA damage . This might be the underlying mechanism of the different phase of cell cycle arrest caused by NCTD.
It has been reported that NCTD can suppress the pAkt or pERK1/2 signaling pathway [19,47]. However, we did not find research describing suppression of both these pathways by NCTD. In the present study, we found that NCTD simultaneously inhibited pAkt and pERK1/2 in TNBC cells. As pAkt and pERK1/2 were both inhibited by NCTD, their potential crosstalk was also blocked, which resulted in effective tumor repression in vitro and in vivo. Thus, this study provides a theoretical basis for the application of NCTD in the treatment of TNBC.
Collectively, the present findings prove that NCTD exerts an anticancer effect in vitro and in vivo by simultaneously suppressing Akt and ERK signaling. We also show that NCTD upregulates the level of soluble signaling factors of SASP in a NF-κB-independent manner, which provides a novel explanation of the molecular mechanism of NCTD.
Conflicts of interest
Ethics approval and consent to participate
Acknowledgements The authors thank Prof. Qian Tao (the Chinese University of Hong Kong, Hong Kong, China) for generously providing cell lines. This study was supported by the National Natural Science Foundation of China (NO. 81572769, NO.81372238), the Natural Science Foundation of Chongqing (2016ZDXM006) and the Scientific Research Foundation of Chongqing Medical University (NO. 201408).
Introduction Psoriasis is an inflammatory skin disease with characteristic skin lesions that usually located on the umbilicus, elbows, scalp and knees [9,22]. It is common in American, Canadian, and European, and threats to the health of 125 million people globally . At present, the treatments of psoriasis mainly includes drug treatment, physical therapy, biological therapy, which is aimed at alleviating symptoms and skin lesions, avoiding repetition, and improving the quality of life of patients . The pathogenesis of psoriasis is related to multiple factors such as heredity, immunity and metabolism after a large number of studies, HLA genetic susceptibility, T cell abnormal activation and differentiation, streptococcal infection, abnormal cell proliferation and lack of apoptosis in keratinocytes are central events in the pathophysiology of psoriasis [23,27]. Psoriasis usually shows erythematous plaques with adherent silvery scales, which is resulted from hyper-proliferation of keratinocytes and infiltration of inflammatory cells . Presently, it is generally believed that keratinocytes plays a key role in the pathogenesis of psoriasis. It is imbalance between apoptosis and proliferation of keratinocytes because lesions of keratinocytes have stronger anti-apoptotic ability . Thus, it is a pathogenic driver of aberrant keratinocyte biology. Keratinocytes apoptosis contributes to elimination of plaque and psoriasis during routine treatment . Dual-specificity phosphatase-1 (DUSP1) belongs to the dual-specificity phosphatase family , which are implicated in inactivating different MAPK family isoforms . DUSP1 plays integral roles in various physiological processes, including cell proliferation, cell cycle arrest, and cell apoptosis in normal and tumor cells . It contributes to carcinogenesis of prostate and lung cancer, yet it suppressed the development of HCC and prevents carcinogenesis of head and neck SCC . Recently, DUSP1 was significantly reduced in psoriatic skin lesions compared with paired samples of non-lesional psoriatic skin . In addition, DUSP1 in dermal MSCs was significantly lower in psoriasis patients than that in healthy individuals , which indicates a relationship between psoriasis and DUSP1.