Targeting oral cancer stemness and chemoresistance by isoliquiritigenin-mediated GRP78 regulation

Abstract

Cancer stem cells (CSCs) are cells that drive tumorigenesis, contributing to metastasis and cancer recurrence as well as resistance to chemotherapy of oral squamous cell carcinomas (OSCC). Therefore, approaches to target CSCs become the subject of intense research for cancer therapy. In this study, we demonstrated that isoliquiritigenin, a chalcone-type flavonoid isolated from licorice root, exhibited more toxicity in oral cancer stem cells (OSCC-CSCs) compared to normal cells. Treatment of isoliquiritigenin not only inhibited the self-renewal ability but also reduced the expression of CSC markers, including the ALDH1 and CD44. In addition, the capacities of OSCC-CSCs to invade, metastasize and grow into a colony were suppressed by isoliquiritigenin. Most importantly, we showed that isoliquiritigenin potentiated chemotherapy along with downregulated expression of an ABC transporter that is associated with drug resistance, ABCG2. Moreover, a combination of isoliquiritigenin and Cisplatin significantly repressed the invasion and colony formation abilities of OSCC-CSCs. Our results suggested that administration of isoliquiritigenin reduced the protein expression of mRNA and membrane GRP78, a critical mediator of tumor biology. Overexpression of GRP78 reversed the inhibitory effect of isoliquiritigenin on OSCC-CSCs. Furthermore, isoliquiritigenin retarded the tumor growth in nude mice bearing OSCC xenografts. Taken together, these findings showed that isoliquiritigenin is an effective natural compound that can serve as an adjunct to chemotherapy for OSCC.

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

“…By means of the selective inhibition of GRP78 ATPase with isoliquiritigenin (a chalcone-type bioflavonoid), it was shown that the binding of GRP78 to β-catenin is necessary to realize the GRP78/β-catenin/ABCG2 pathway in breast CSCs, which contributes to their drug resistance [232]. Later, GRP78-downregulating treatments with isoliquiritigenin enabled Hu et al [233] to discover the essential role of GRP78 in the expression of CD44, ALDH1, and ABCG2 (all are stemness markers) and the ability for invasion and metastatic spread and resistance to chemotherapy in CSCs from oral squamous cell carcinomas. Silencing of GRP78 suppressed self-renewal and radioresistance of glioma CSCs, which was due to the increase in the microRNA-205 level [234].…”

“…In another study dedicated to targeting GRP78 in glioblastoma CSCs, pterostilbene, a plant-derived stilbenoid and dietary component, impaired self-renewal and radioresistance in glioblastoma CSCs through modulating GRP78 signaling and the GRP78/miR-205 axis [234]. Another plant-derived compound, isoliquiritigenin (a chalcone-type bioflavonoid), was shown to suppress both the self-renewal ability and the expression of cancer stemness markers, such as CD44 and ALDH1, in CSCs from oral squamous cell carcinoma; in addition, the invasive and metastatic capacities became impaired in isoliquiritigenin-treated oral CSCs [233]. The anti-stemness effects of isoliquiritigenin were associated with the downregulation of GRP78 (both intracellular and membrane-bound GRP78), whereas those effects could be reversed by GRP78 overexpression [233].…”

“…Another plant-derived compound, isoliquiritigenin (a chalcone-type bioflavonoid), was shown to suppress both the self-renewal ability and the expression of cancer stemness markers, such as CD44 and ALDH1, in CSCs from oral squamous cell carcinoma; in addition, the invasive and metastatic capacities became impaired in isoliquiritigenin-treated oral CSCs [233]. The anti-stemness effects of isoliquiritigenin were associated with the downregulation of GRP78 (both intracellular and membrane-bound GRP78), whereas those effects could be reversed by GRP78 overexpression [233]. In turn, ovatodiolide (a macrocyclic diterpenoid compound) was able to impair the GRP78 upregulation associated with YAP1 expression, which confers the CSC phenotype in hepatocellular carcinoma cells [228].…”

“…In turn, ovatodiolide (a macrocyclic diterpenoid compound) was able to impair the GRP78 upregulation associated with YAP1 expression, which confers the CSC phenotype in hepatocellular carcinoma cells [228]. Overall, such anti-GRP78 activity of the natural compounds [228,233,234] seems pretty beneficial because they may be used as low-toxicity bioavailable agents for in vivo targeting of CSCs. In this connection, ovatodiolide is noteworthy, as besides its anti-GRP78 activity [228], this natural substance may also decrease HSP27 expression in CSCs [156].…”

“…Besides, plasma membrane-bound GRP78 has been found in CSCs from oral squamous cell carcinoma [233] and in CSCs from head and neck cancers [245]. It is asserted in the latter reference that cell surface-associated endogenous GRP78 is a determinant of cancer stemness development, which can be reversed by the GRP78 interactome protein, progranulin: Being expressed on the cancer cell surface, GRP78 is conducive to cancer stemness, but interactions of GRP78 with progranulin, if they occur, retain a non-stem cancer cell phenotype [245].…”