Kazinol C from Broussonetia kazinoki stimulates autophagy via endoplasmic reticulum stress-mediated signaling

Abstract

Autophagy modulators are considered putative therapeutic targets because of the role of autophagy in cancer progression. Kazinol C, a 1,3-diphenylpropane from the plant Broussonetia kazinoki , has been shown to induce apoptosis in colon cancer cells through the activation of AMPK at high concentrations. In the present study, we found that Kazinol C induced autophagy through endoplasmic reticulum stress-mediated unfolded protein response signaling in several normal and cancer cell lines at low concentrations of Kazinol C that did not induce apoptosis. Kazinol C activated the transducers of unfolded protein response signaling, leading to target gene expression, LC3-II conversion, and TFEB nuclear translocation. Chemical inhibition of endoplasmic reticulum stress reduced LC3-II conversion. In addition, blockade of autophagy by knockout of Atg5 or treatment with 3-MA enhanced Kazinol C-induced apoptosis. In summary, we have uncovered Kazinol C as a novel autophagy inducer and confirmed the role of autophagy as a cellular stress protector.

The Genus Broussonetia: An Updated Review of Phytochemistry, Pharmacology and Applications

“…From this evidence, it is clear that AMPK is a major regulator of energy metabolic pathways and plays an important role in the regulation of autophagy. In this work, the active compound kazinol C, isolated from BK whole herbs or root barks, could markedly induce apoptosis in colon cancer cells by activating AMPK phosphorylation [2,88].…”

“…Broussonetia is one of the most significant genera in the Moraceae family, a member of the Urticales order. The genus is composed of eleven species, comprising Broussonetia papyrifera (BP) (see Figure 1) [1], Broussonetia kazinoki (BK) (see Figure 2) [2], Broussonetia zeylanica (Thwaites) Corner (BZ) [3], Broussonetia luzonica (Blanco) Bureau (BL) [4], Broussonetia rupicola F.T. Wang and Tang (BR), Broussonetia kurzii (Hook.f.)…”

“…The genus of Broussonetia has been found to present 338 compounds, including flavonoids, polyphenols, alkaloids, terpenoids, steroids, and others. Active compounds isolated from Broussonetia have been demonstrated to have several biological properties, including antitumor [2], antioxidant [13], anti-inflammation [14], antidiabetic [15], anti-obesity [16], antibacterial [17], and antiviral activities [18], as well as being used for skin whitening [19] and against skin wrinkles, as well as many other uses. In terms of representative applications, Broussonetia species could be used as forage for cattle, Hu rams and lambs, growing goats, and other animals because of the high content of protein and fiber [20,21].…”

Crosstalk between endoplasmic reticulum stress response and autophagy in human diseases

“…Many ER stress inducers, such as tunicamycin, arachidonic acid, DFS, and Kazinol C, are known to simultaneously induce autophagy (Kwon et al 2020 ; Lee et al 2022 ). ER stress and autophagy are two major response pathways to cellular stress that are closely related to each other.…”

“…Similarly, the anticancer effect of lexibulin on osteosarcoma is also limited by ER stress-induced autophagy, and its effect on cancer cell death is more potent when used together with an autophagy inhibitor (Wang et al 2019 ). Additionally, research on substances with various anticancer effects has demonstrated that ER stress induction and autophagy inhibition play an important role in the death of various cancer cells, such as liver, colorectal, and prostate cancer (Kwon et al 2020 ; Lee et al 2022 ).…”