Maprotiline Suppresses Hepatocellular Carcinoma Via CRABP1-mediated Functional Mechanism

Hepatocellular carcinoma(HCC)ranks third among the main causes of cancer-related death worldwide.It has poor treatment prognosis,frequent postoperative recurrence and drug resistance.There is an urgent need for more effective anti HCC drugs.In this paper,we used a small molecule drug library composed of 1056 FDA approved drugs to screen potential anti HCC drugs.Maprotiline,a tetracycline antidepressant,is a highly selective norepinephrine reuptake blocker with strong antidepressant effect,and its anticancer effect has never been reported.We studied the anticancer potential of maprotiline in HCC cell lines Huh7 and Hep G2.We found that maprotiline can not only significantly inhibit cell proliferation,clone formation and metastasis in vitro,but also play an antitumor role in vivo.In addition to the anti-tumor effect alone,maprotiline can also enhance the killing effect of sorafenib on liver cancer cells.Our depth studies have shown that maprotiline significantly reduces the phosphorylation of sterol regulatory element binding protein 2(SREBP2)by inhibiting ERK signaling pathway,resulting in the reduction of cholesterol biosynthesis and finally inhibiting the growth of hepatocellular carcinoma cells.In addition,we found that cellular retinoic acid binding protein 1(CRABP1)may be a direct target of maprotiline.This study provides the evidence that maprotiline may directly bind to CRABP1,inhibit its biological activity,inhibit Erk-SREBP2 signal pathway and reduce cholesterol biosynthesis,and finally inhibit the growth and metastasis of hepatocellular carcinoma cells,which supports the possibility of redefining maprotiline as an anti hepatoma drug in the treatment of hepatocellular carcinoma.