Norcantharidin alone or in combination with crizotinib induces autophagic cell death in hepatocellular carcinoma by repressing c-Met-mTOR signaling.

Chao-Yue Sun,Xie-Qi Wang,Zu-Qing Su,Ying Zhu,Guang-Juan Zheng,Xiao-Feng Li,Cai-Yun Li,Li-Peng Tang,Bing Feng,Hong-Mei Yang

doi:10.18632/oncotarget.22935

Chao-Yue Sun, Xie-Qi Wang + Show 8 more

Open Access

https://doi.org/10.18632/oncotarget.22935

Copy DOI

Journal: Oncotarget	Publication Date: Dec 4, 2017
Citations: 25	License type: cc-by

Affiliation: Guangzhou University of Chinese Medicine

Abstract

There is an urgent need for effective molecular therapies for hepatocellular carcinoma (HCC), the third-leading cause of cancer-related deaths worldwide. Norcantharidin (NCTD), a demethylated derivative of cantharidin, reportedly exhibits anticancer activity against various types of tumors, including HCC, though the mechanisms involved remain largely unknown. Here, we report that NCTD reduces viability of human MHCC-97H (97H) and HepG2 HCC cells, and induces cell death by triggering high levels of autophagy. Moreover, a significant attenuation of tumor growth was observed after NCTD treatment of HepG2 tumors in vivo, and this effect was enhanced by co-treatment with the c-Met inhibitor crizotinib. Interestingly, western blot analyses showed that the cytotoxic autophagy induced by NCTD correlates with a reduction in the phosphorylation status of both c-Met and m-TOR. These results suggest that cytotoxic autophagy resulting from inhibition of c-Met/mTOR signaling may be achieved in HCC by combined NCTD and crizotinib administration. Further studies to validate the therapeutic potential of this approach are warranted.

Highlights

Hepatocellular carcinoma (HCC), the third leading cause of cancer-related death worldwide, is characterized by high metastatic and recurrence rates [1]
These results suggest that cytotoxic autophagy resulting from inhibition of c-Met/mTOR signaling may be achieved in hepatocellular carcinoma (HCC) by combined NCTD and crizotinib administration
We present evidence that NCTD downregulates of the c-Met and mTOR signaling pathways and induces cytotoxic autophagy in HCC cells both in vitro and in vivo, an effect exacerbated by co-treatment with the c-Met inhibitor crizotinib

Summary

Introduction

Hepatocellular carcinoma (HCC), the third leading cause of cancer-related death worldwide, is characterized by high metastatic and recurrence rates [1]. Despite the development of new therapeutic strategies and improved patient care, the 5-year survival rate associated with HCC remains dismal [2]. More worrisome is the fact that the death rate of HCC is increasing consistently, while the mortality associated with other malignancies is falling steadily [3]. Aberrant activation of c-Met signaling is responsible for the growth, progression, invasion, and poor prognosis of various types of tumors including HCC [7]. Overexpression of www.impactjournals.com/oncotarget c-Met is frequently observed in HCC patients, and has underpinned several clinical investigations attempting to inhibit signaling through HGF/c-Met [8]. Inhibition of c-Met signaling is regarded as one of the most promising anticancer therapeutic options for the treatment of HCC [9]. Activation of the associated pathways is contextdependent and regulates critical cell functions such as proliferation, motility, and apoptosis [10]

Methods

Results

Conclusion