Cordycepin down-regulates multiple drug resistant (MDR)/HIF-1α through regulating AMPK/mTORC1 signaling in GBC-SD gallbladder cancer cells.

Wei-Ding Wu,Da-Jian Zhao,Zhi-Ming Hu,De-Fei Hong,Cheng-Wu Zhang,Min-Jie Shang,Dong-Sheng Huang

doi:10.3390/ijms150712778

Wei-Ding Wu, Da-Jian Zhao + Show 5 more

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https://doi.org/10.3390/ijms150712778

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Abstract

Gallbladder cancer is the most common malignancy of the bile duct, with low 5-year survival rate and poor prognosis. Novel effective treatments are urgently needed for the therapy of this disease. Here, we showed that cordycepin, the bioactive compound in genus Cordyceps, induced growth inhibition and apoptosis in cultured gallbladder cancer cells (Mz-ChA-1, QBC939 and GBC-SD lines). We found that cordycepin inhibited mTOR complex 1 (mTORC1) activation and down-regulated multiple drug resistant (MDR)/hypoxia-inducible factor 1α (HIF-1α) expression through activating of AMP-activated protein kinase (AMPK) signaling in gallbladder cancer GBC-SD cells. Contrarily, AMPKα1-shRNA depletion dramatically inhibited cordycepin-induced molecular changes as well as GBC-SD cell apoptosis. Further, our results showed that co-treatment with a low concentration cordycepin could remarkably enhance the chemosensitivity of GBC-SD cells to gemcitabine and 5-fluorouracil (5-FU), and the mechanism may be attributed to AMPK activation and MDR degradation. In summary, cordycepin induces growth inhibition and apoptosis in gallbladder cancer cells via activating AMPK signaling. Cordycepin could be a promising new drug or chemo-adjuvant for gallbladder cancer.

Highlights

Gallbladder cancer is the most frequent malignancy of the bile duct [1]
We present evidence that AMPK activation by cordycepin induces mTOR complex 1 (mTORC1) in-activation and hypoxia-inducible factor 1α (HIF-1α)/multiple drug resistant (MDR) degradation, which mediates GBC-SD gallbladder cancer cell growth inhibition and apoptosis
These results show that cordycepin inhibits gallbladder cancer cell survival

Summary

Introduction

Gallbladder cancer is the most frequent malignancy of the bile duct [1]. It is a highly aggressive and lethal neoplasm associated with high mortality rate and poor prognosis [2,3,4]. Despite recent progresses in diagnostic and therapeutic approaches, the 5-year overall survival is generally low [2]. The surgical resection is the only curative therapy for gallbladder cancer in clinical practices; a large proportion of patients will develop recurrences or even metastasis following surgery and/or traditional chemotherapy or radiotherapy [5,6]. Novel effective therapeutic drugs and adjuvants are urgently needed for this devastating disease

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