Compound C induces protective autophagy in human cholangiocarcinoma cells via Akt/mTOR‐independent pathway

Abstract

Compound C, a well-known inhibitor of AMP-activated protein kinase (AMPK), has been reported to exert antitumor activities in some types of cells. Whether compound C can exert antitumor effects in human cholangiocarcinoma (CCA) remains unknown. Here, we demonstrated that compound C is a potent inducer of cell death and autophagy in human CCA cells. Autophagy inhibitors increased the cytotoxicity of compound C towards human CCA cells, as confirmed by increased LDH release, and PARP cleavage. It is notable that compound C treatment increased phosphorylated Akt, sustained high levels of phosphorylated p70S6K, and decreased mTOR regulated p-ULK1 (ser757). Based on the data that blocking PI3K/Akt or mTOR had no apparent influence on autophagic response, we suggest that compound C induces autophagy independent of Akt/mTOR signaling in human CCA cells. Further study demonstrated that compound C inhibited the phosphorylation of JNK and its target c-Jun. Blocking JNK by SP600125 or siRNA suppressed autophagy induction upon compound C treatment. Moreover, compound C induced p38 MAPK activation, and its inhibition promoted autophagy induction via JNK activation. In addition, compound C induced p53 expression, and its inhibition attenuated compound C-induced autophagic response. Thus, compound C triggers autophagy, at least in part, via the JNK and p53 pathways in human CCA cells. In conclusion, suppresses autophagy could increase compound C sensitivity in human CCA.

Therapeutic Potential of Autophagy Modulation in Cholangiocarcinoma

“…Another advantage of inhibiting autophagy relies on the blockage of the protective mechanism mediated by autophagy activation induced by different drugs. A wide variety of anticancer compounds induce protective autophagy in CCA [145][146][147] including chemotherapy [106,141] and the inhibition of autophagy accelerated apoptosis and chemosensitized CCA cells. This opens up different possibilities to design combinatory treatments that could block this protective autophagy and enhance the therapeutic effects of different drugs in addition to diminishing tumor dissemination.…”

“…A wide variety of anticancer compounds induce autophagy in CCA, making it necessary to discern whether it is a protective autophagy promoted by cancer cells as an adaptive mechanism, therefore inhibition of autophagy leads to a potentiation of their cytotoxic effects, or if on the contrary, mediates drug mechanism of cancer cell death induction. Several compounds that show anticancer efficacy on CCA cells such as norcantharidin [145], compound C [146], vorinostat [147] or cisplatin [106,141] induce the activation of protective autophagy in CCA cells, and pharmacological inhibition of autophagic process enhances these drugs anti-cancer capacity, accelerating apoptosis and sensitizing cell to chemotherapy. The combination of these drugs with autophagy inhibitors offers an attractive therapeutic strategy.…”

The Role of Autophagy in Acute Myocardial Infarction

“…The Class I PI3K-mammalian target of rapamycin (mTOR) signaling pathway, a classical inhibitory pathway, is triggered in the presence of nutrient enrichment, to stimulate the activation of mTOR and the mTOR complex (mTORC1) via protein kinase B (Akt) pathway, thus inhibiting the formation of the Atg1 complex (Kaur and Sharma, 2017; Perez-Alvarez et al., 2018). The other classical signaling pathway of autophagy is induced by AMP-activated protein kinase (AMPK), a sensor of stress and nutrient input, which promotes the occurrence of autophagy process through activating the ULK1 kinase complex by inactivating mTORC1 or phosphorylating ULK1 at various serine residues (Dodson et al., 2013; Zhao et al., 2018a). So far, several kinds of agents have been developed for the blockade or induction of autophagy in different mechanisms, such as rapamycin, chloroquine, bafilomycin A1, and 3-methyladenine (3-MA), thus largely facilitating the fundamental study of autophagy (Germic et al., 2017; Bhat et al., 2018; Zhao et al., 2018b).…”

Diverse Functions of Autophagy in Liver Physiology and Liver Diseases

“…Additionally, p53 was demonstrated to activate autophagy in CCA cells, and the repression of p53 was reported to enhance the chemosensitivity in nutrient-deprived CCA cells through downregulating autophagy (Table 4) [535]. In line with this study, compound C (a pharmacological inhibitor of AMPK) treatment in human CCA cells was shown to induce p53-dependent autophagy to protect cells from apoptosis (Table 4) [536]. On the contrary, autophagy was indicated to participate in microRNA (miR)-124-induced cell death in human CCA cells (Table 4) [537] and in dihydroartemisinin-triggered cell death of human CCA cells through the death-associated protein kinase (DAPK)–Beclin 1 pathway (Table 4) [538].…”