Abstract
The current research studied the potential effect of autophagy on icaritin-induced anti-colorectal cancer (CRC) cell activity. Treatment of icaritin in both primary and established (HT-29) CRC cells induced feedback activation of autophagy, evidenced by p62 degradation, Beclin-1 and autophagy-related gene-5 (ATG-5) upregulation, as well as light chain 3B (LC3B)-GFP puncta formation. Pharmacological inhibiting of autophagy dramatically potentiated icaritin-induced CRC cell death and apoptosis. Meanwhile, shRNA-mediated knockdown of Beclin-1 or ATG-5 also sensitized icaritin-induced CRC cell death and apoptosis. Icaritin activated AMP-activated protein kinase (AMPK) signaling in CRC cells, functioning as the upstream signaling for autophagy activation. shRNA/siRNA-mediated knockdown of AMPKα1inhibited icaritin-induced autophagy activation, but exacerbated CRC cell death. On the other hand, the AMPK activator compound 13 (C13) or the autophagy activator MHY1485 attenuated icaritin-induced cytotoxicity. In nude mice, icaritin (oral administration)-induced HT-29 tumor growth inhibition was potentiated when combined with AMPKα1 shRNA knockdown in tumors. We conclude that feedback activation of AMPK-autophagy pathway could be a primary resistance factor of icaritin.
Highlights
The colorectal cancer (CRC) has long been a major health problem in both Eastern and Western countries [1,2,3]
Icaritin activated AMP-activated protein kinase (AMPK) signaling in CRC cells, functioning as the upstream signaling for autophagy activation. shRNA/siRNA-mediated knockdown of AMPKα1inhibited icaritin-induced autophagy activation, but exacerbated CRC cell death
In order to test the potential effect of icaritin on autophagy, Western blot assay was performed to test expression of autophagy-associated proteins in icaritintreated cells
Summary
The colorectal cancer (CRC) has long been a major health problem in both Eastern and Western countries [1,2,3]. Our group [10] and others [1, 8] have been focusing on exploring novel anti-CRC agents. Studies have tested its biological functions in different experimental settings, including its anti-cancer activity [12,13,14]. Our recent study has demonstrated that icaritin could inhibit CRC cells in vitro and in vivo [10]. We found that icaritin activated JNK-dependent mitochondrial permeability transition pore (mPTP) necrosis pathway to kill CRC cells [10]
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