Cordycepin Down-Regulates Multiple Drug Resistant (MDR)/HIF-1α through Regulating AMPK/mTORC1 Signaling in GBC-SD Gallbladder Cancer Cells

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.

Knockdown of MAGEA6 Activates AMP-Activated Protein Kinase (AMPK) Signaling to Inhibit Human Renal Cell Carcinoma Cells

“…AMPK-mediated autophagy could be through direct mechanism (phosphorylation of Ulk1) and/or indirect mechanisms (mTORC1 inhibition) [61, 62]. Recent studies have confirmed that AMPK activation could lead to degradation of several oncogenic proteins or oncogenes [18, 19]. Further studies will be needed to explore the downstream effectors of AMPK that mediate MAGEA6 shRNA-induced inhibition of RCC cells.…”

“…Recent studies have also proposed AMPK as a key tumor suppressor protein [12-14]. Activated AMPK exerts anti-cancer functions via different mechanisms, including mTOR complex 1 (mTORC1) inhibition [15], autophagy induction [16], p53 activation [17], as well as degradation of several key oncogenic proteins [18, 19]. AMPK can also modulate epithelial-to-messenchymal transition (EMT) via regulating Akt-MDM2-Foxo3 signaling [20].…”

Down-regulating HIF-1α by lentivirus-mediated shRNA for therapy of triple negative breast cancer

“…Multidrug resistance (MDR) is a main cause of breast cancer chemotherapy failure. 41 Hypoxia induces cellular adaptations which contribute to cancer progression and chemoresistance, with one of these adaptations being the expression of multidrug resistance proteins such as ABC transporters. 42 Evidence of MDR-1 or MRP1 upregulation through HIF-1 under hypoxia has recently been highlighted.…”

Medicinal Value of Cordyceps sinensis

“…The conclusion was drawn that inhibition of cell proliferation and further apoptosis of SW480 and SW620 cells were induced by cordycepin [7]. Similar action of cordycepin was also demonstrated in gallbladder cancer cells in vitro with its additional effect in down regulation of multidrug resistance (MDR) expression [8]. Its mode of action was by activation of AMPK (adenosine monophosphate activated protein kinase) signaling which lead to degradation of MDR/ HIF-1α (hypoxia inducible factor), cordycepin also inhibited the mTORC1 (mammalian target of rapamycin complex 1) in gallbladder cancer cell which leads to loss of cancer cell viability and apoptosis.…”