Betulinic Acid Inhibits the Stemness of Gastric Cancer Cells by Regulating the GRP78-TGF-β1 Signaling Pathway and Macrophage Polarization

Abstract

Cancer stemness is the process by which cancer cells acquire chemoresistance and self-renewal in the tumor microenvironment. Glucose-regulated protein 78 (GRP78) is a biomarker for gastric cancer and is involved in cancer stemness. By inducing cancer stemness in various types of cancer, the polarization of macrophages into tumor-associated macrophages (TAMs) controls tumor progression. Betulinic acid (BA) is a bioactive natural compound with anticancer properties. However, whether GRP78 regulates TAM-mediated cancer stemness in the tumor microenvironment and whether BA inhibits GRP78-mediated cancer stemness in gastric cancer remain unknown. In this study, we investigated the role of GRP78 in gastric cancer stemness in a tumor microenvironment regulated by BA. The results indicated that BA inhibited not only GRP78-mediated stemness-related protein expression and GRP78-TGF-β-mediated macrophage polarization into TAMs, but also TAM-mediated cancer stemness. Therefore, BA is a promising candidate for clinical application in combination-chemotherapy targeting cancer stemness.

Tumour‐associated macrophages in gastric cancer: From function and mechanism to application

“…Accumulative research has reported that EVs containing microRNAs, circular RNAs, long non‐coding RNAs (lncRNAs) or proteins derived from GC cells regulated the polarisation of TAMs after the internalisation by macrophages 52,64–71 . Notably, natural compounds extracted from plants, such as flavokawain B, sophoridine, diosmetin, elian granules and betulinic acid, were found to enhance the polarisation of M1 TAMs 72–76 . Additionally, pentraxin‐3 was found to inhibit the polarisation of M2 TAMs by reducing cells secreting IL‐4 and IL‐10 via the inhibition of the phosphorylation of JNK1/2 in GC cells 77 .…”

“…52,[64][65][66][67][68][69][70][71] Notably, natural compounds extracted from plants, such as flavokawain B, sophoridine, diosmetin, elian granules and betulinic acid, were found to enhance the polarisation of M1 TAMs. [72][73][74][75][76] Additionally, pentraxin-3 was found to inhibit the polarisation of M2 TAMs by reducing cells secreting IL-4 and IL-10 via the inhibition of the phosphorylation of JNK1/2 in GC cells. 77 IL-4, a cytokine, was widely reported to elicit M2 polarisation, while Zhao and Liu demonstrated that the IL-4-stimulated heparin binding-epidermal growth factor (HB-EGF)-dependent transactivation of EGFR inhibited the polarisation of M2 TAMs induced by IL-4-stimulated STAT6 activation.…”

Multidimensional pan-cancer analysis of HSPA5 and its validation in the prognostic value of bladder cancer

“…Cell surface GRP78-targeted CAR-T cells have also been shown to be effective in treating human pancreatic cancer [ 14 ]. In addition, HSPA5 has been shown to affect the stemness profile of cancer cells in esophageal, glioblastoma, gastric and breast cancers [ [15] , [16] , [17] , [18] ].…”