Targeting liver-tumor initiation cells via hampering the lipogenesis pathways through stearoyl-CoA desaturase

Abstract

Hepatocellular carcinoma is one of the most lethal cancers in the world. Currently, Sorafenib is the only FDA-approved molecularly targeted drug for treating patients with advanced HCC. However, it only extends patients’ life by a median of 3-4 months. Tumor relapse will acquire resistance to this drug and thus finding new therapeutic regimes is crucial in combating against this deadly cancer. Increasing evidence showed that tumor initiating cells (TICs) or cancer stem cells (CSCs) are intrinsically resistant to conventional chemotherapies. Identification of the signalling pathways that maintain the functions of CSCs provides potential targets for treatment of HCC. For this purpose, our team has established serial passages of hepatospheres combined with chemotherapeutic regimens as a strategy to enrich liver CSCs population. Furthermore, using cDNA microarray, we found upregulation of several key enzymes in lipogenesis in enriched CSCs population, among which Stearoyl CoA desaturase-1 (SCD1), the enzyme involved in the conversion of saturated into monounsaturated fatty acids, was most significantly upregulated. In human HCCs, 60% was found to be overexpressed (> 2-fold) when compared with the non-tumour liver counterparts. Patients with overexpressed SCD1 in their tumors had shorter disease-free survival. Using overexpression and knockdown approaches, SCD1 was found to regulate the traits of CSCs, including tumorigenicity, self-renewal, chemoresistance and expression of liver CSCs markers. The results were also validated by the employment of SCD1 inhibitor A939572. Furthermore, SCD1 was markedly upregulated in our established sorafenib-resistant patient-derived xenograft (PDTX) model, and its overexpression predicts the clinical response of HCC patients to sorafenib. Pharmacological inhibition of SCD1 not only suppressed self-renewal ability but also consistently enhanced the sensitivity of sorafenib. Using a PDTX (PDTX#1), we found that a novel SCD1 inhibitor SetA04 demonstrated maximal growth suppressive effect when combined with sorafenib treatment. By comparing the genetic profiles between SCD1 knockdown cells and control cells with RNA sequencing analysis, we found upregulation of ER stress-induced activation of the unfolded protein response (UPR) in SCD1 knockdown cells. Suppression of SCD1 forced the liver CSCs to differentiate via induction of ER stress, resulting in their enhanced sensitivity to sorafenib both in vitro and in vivo. In summary, SCD1-induced ER stress may specifically increase the sensitivity of liver CSCs to the effects of sorafenib treatment. Targeting SCD1 in combination with sorafenib may be a novel therapeutic regimen against HCC.