Abstract
Ganoderma lucidum exerts antitumor activity, but the mechanism of G. lucidum polysaccharides on cancer is unclear. Here, we demonstrated that a fucose-containing fraction of Ling-Zhi (FFLZ) reduced tumor size and suppressed metastasis in vivo. Furthermore, FFLZ inhibited breast cancer cell migration and altered the epithelial-to-mesenchymal transition (EMT) phenotype. Transforming growth factor-β receptor (TGFR) pathways act as key mediators to promote tumor progression and metastasis. We found that FFLZ down-regulated TGFR and downstream signaling pathways, including the phosphorylation of Smad2/3 and the expression of Smad4. In an investigation of the underlying mechanisms, we found that FFLZ enhanced the Smurf2-dependent ubiquitination of TGFR by disrupting the balance of the lipid rafts, promoted the “re-localization” of the TGFR to the caveolae, and facilitated the degradation of TGFR. Together, our data indicated that FFLZ is associated with the inhibition of EMT and the prevention of metastasis by promoting ubiquitination-dependent TGFR degradation and abolishing TGFR signaling pathways. Moreover, the combination of FFLZ and trastuzumab synergistically inhibited the viability of certain trastuzumab-resistant human breast cancer cells. In summary, our current findings indicate that FFLZ is a potential therapeutic or dietary supplemental agent for cancer patients and that it functions via the caveolin-1/Smad7/Smurf2-dependent ubiquitin-mediated degradation of TGFR.
Highlights
Ganoderma lucidum has been used as a traditional Asian medicine to promote good health and longevity[1]
Because it has been reported that TGFRI ubiquitination is promoted via lipid rafts/caveolae-mediated endocytosis[27], we further examined whether lipid rafts/caveolae were involved in the fraction of Ling-Zhi (FFLZ)-mediated degradation of TGFRI
We found that TGFRI protein was dramatically increased in the LR fraction of FFLZ-treated cells, and much more ubiquitinated TGFRI was immunoprecipitated from the FFLZ-treated lipid rafts/caveolin fractions than from the control groups (Fig. 5B, lane 2 vs. 4, IP: TGFRI)
Summary
Ganoderma lucidum (a medicinal fungus, aka Ling-Zhi in Chinese) has been used as a traditional Asian medicine to promote good health and longevity[1]. Recent findings indicate that the inhibition of the activity of transforming growth factor-β1 (TGFβ) and/or TGFβreceptors (TGFR) enhances the action of chemotherapy against triple-negative breast cancer[5]. A two-step regulation of TGFR has been proposed: in the first step, TGFR perform trafficking via the clathrin-mediated or lipid rafts/caveolae-mediated pathways to activate or inhibit signaling. 5. It is important that the inhibition of TGFβand/or TGFR activity enhances the action of chemotherapy against triple-negative breast cancer[5]. FFLZ inhibits migration during the EMT by suppressing TGFR-mediated signaling via the lipid rafts/caveolae-mediated ubiquitin-dependent degradation of TGFR. Our research revealed that the combination of trastuzumab and FFLZ exhibits a synergetic antitumor effect in trastuzumab-resistant and/or triple-negative breast cancer cells, suggesting that this combination might provide a novel regimen for clinical breast cancer treatment
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