Targeted therapy of the AKT kinase inhibits esophageal squamous cell carcinoma growth in vitro and in vivo

Abstract

Esophageal cancer, a leading cause of cancer death worldwide, is associated with abnormal activation of the AKT signaling pathway. Xanthohumol, a prenylated flavonoid tested in clinical trials, is reported to exert anti‐diabetes, anti‐inflammation and anticancer activities. However, the mechanisms underlying its chemopreventive or chemotherapeutic effects remain elusive. In the present study, we found that xanthohumol directly targeted AKT1/2 in esophageal squamous cell carcinoma (ESCC). Xanthohumol significantly inhibited the AKT kinase activity in an ATP competitive manner, which was confirmed in binding and computational docking models. KYSE70, 450 and 510 ESCC cell lines highly express AKT and knockdown of AKT1/2 suppressed proliferation of these cells. Treatment with xanthohumol inhibited ESCC cell growth and induced apoptosis and cell cycle arrest at the G1 phase. Xanthohumol also decreased expression of cyclin D1 and increased the levels of cleaved caspase‐3, ‐7 and ‐PARP as well as Bax, Bim s and cytochrome c in ESCC cells by downregulating AKT signaling targets, including glycogen synthase kinase 3 beta (GSK3β), mammalian target of rapamycin, and ribosomal protein S6 (S6K). Furthermore, xanthohumol decreased tumor volume and weight in patient‐derived xenografts (PDXs) that highly expressed AKT, but had no effect on PDXs that exhibited low expression of AKT in vivo . Kinase array results showed that xanthohumol treatment decreased phosphorylated p27 expression in both ESCC cell lines and PDX models. Taken together, our data suggest that the inhibition of ESCC tumor growth with xanthohumol is caused by targeting AKT. These results provide good evidence for translation toward clinical trials with xanthohumol.

Xanthohumol, a Prenylated Flavonoid from Hops, Induces DNA Damages in Colorectal Cancer Cells and Sensitizes SW480 Cells to the SN38 Chemotherapeutic Agent

“…To determine whether Xn exerts a potential adjuvant action with chemotherapeutic drugs, we first analyzed its ability to inhibit the proliferation of three CRC cell lines. Some reports have previously described a potential antiproliferative property for Xn that is highly dependent on cell lines, times of treatment, and concentrations of this prenylated chalcone [19,28,29]. For example, Xn at 10 µM inhibited cell proliferation in the thyroid cancer TPC-1 cell line, supporting a potential action against carcinogenesis, while approximately 100 µM Xn decreased cell viability and the main proapoptotic process [30].…”

ACTL6A Promotes the Proliferation of Esophageal Squamous Cell Carcinoma Cells and Correlates with Poor Clinical Outcomes

“…Additionally, S6K1/pS6 is downstream of the AKT/mTOR pathway, which contributes to the proliferation of esophageal cancer cells, supporting the role of S6K1 in cancer cell proliferation. 36 In addition, liver-specific S6 knockout in mice led to severe cell cycle arrest, indicating the critical role of S6 in cell cycle progression. 37 At present, the direct regulatory mechanism by which ACTL6A regulates the phosphorylation of S6 to control cell cycle regulators remains unclear.…”

Thymoquinone inhibits the proliferation and invasion of esophageal cancer cells by disrupting the AKT/GSK‐3β/Wnt signaling pathway via PTEN upregulation

“…Li B et al reported that the AKT pathway were associated with increased cancer cell invasiveness, demonstrating that this pathway may be a valid target in the treatment of metastatic ESCC (Li et al, 2017). The growth of esophageal cancer can be significantly inhibited by targeting the AKT kinase (Liu et al, 2019).…”