EGFR‑associated pathways involved in traditional Chinese medicine (TCM)‑1‑induced cell growth inhibition, autophagy and apoptosis in prostate cancer

Abstract

Traditional Chinese medicine (TCM) has the synergistic effect of the combination of a single ingredient and a monomer, and systemic and local therapeutic effects in cancer treatment, through which TCM is able to enhance the curative effect and reduce the side effects. The present study analyzed the effect of TCM‑1 (an anti‑cancer TCM) on prostate cancer (PCa) cell lines, and studied in detail the mechanism of cell death induced by TCM‑1 in vitro and in vivo. From the present results, it was identified for the first time, to the best of our knowledge, that TCM‑1 arrested the cell cycle at the G1 phase, decreased cell viability and increased nuclear rupture in a dose‑dependent manner; these effects finally resulted in apoptosis in PCa cells. At the molecular level, the data demonstrated that TCM‑1 competitively acted on epidermal growth factor receptor (EGFR) with EGF, and suppressed the auto‑phosphorylation and activity of EGFR. Inhibition of EGFR further suppressed the downstream phosphatidylinositol 3‑kinase (PI3K)/RAC‑α serine/threonine‑protein kinase (AKT) and RAF proto‑oncogene serine/threonine‑protein kinase/extracellular signal regulated kinase signaling pathways and resulted in a decrease in the phosphorylated‑forkhead box protein O1 (at Ser256, Thr24 and Ser319) expression level, and induced cell growth inhibition and apoptosis by regulating the expression of apoptosis‑and cell cycle‑associated genes. In addition, TCM‑1 markedly inhibited the PI3K/AKT/serine/threonine‑protein kinase mTOR signaling pathway and induced cell autophagy by downregulating the phosphorylation of p70S6K and upregulating the levels of Beclin‑1 and microtubule‑associated protein light chain‑3II. In vivo, the TCM‑1‑treated group exhibited a significant decrease in tumor volume compared with the negative control group in subcutaneous xenograft nude mice by inhibiting EGFR‑associated signaling pathways. Therefore, the bio‑functions of Chinese medicine TCM‑1 in inducing PCa cell growth inhibition, autophagy and apoptosis suggested that TCM‑1 may have clinical potential for the treatment of patients with PCa.

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