Cryptocaryone induces apoptosis in human hepatocellular carcinoma cells by inhibiting aerobic glycolysis through Akt and c-Src signaling pathways

Chen-Lin Yu ^{1, #}, Yu-Wei Lai ^{2, 3, #}, Jih-Jung Chen ^{4, 5}, Jie-Jen Lee ⁶, Tsung-Hsien Chou ^{7, 8}, Chen-Chen Huang ¹, Shih-Chia Liu ⁹, Guang-Wei Chen ¹⁰, Chung‐Hsin Tsai ^{6, 11, *}, Shih-Wei Wang ^{1, 6, 12, 13, *}

¹ Institute of Biomedical Science, MacKay Medical College, New Taipei City, Taiwan

² Division of Urology, Taipei City Hospital Renai Branch, Taipei, Taiwan.

³ Department of Urology, School of Medicine, National Yang Ming Chiao Tun University, Taipei, Taiwan

⁴ Department of Pharmacy, School of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan.

⁵ Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.

⁶ Department of Medicine, MacKay Medical College, New Taipei City, Taiwan

⁷ Public Health Bureau, Pingtung County Government, Pingtung, Taiwan.

⁸ Graduate Institute of Pharmaceutical Technology, Tajen University, Pingtung, Taiwan.

⁹ Division of Pediatric Orthopedics, Department of Orthopedic Surgery, MacKay Memorial Hospital, Taipei, Taiwan.

¹⁰ Department of Chinese Medicine, MacKay Memorial Hospital, Taipei, Taiwan

¹¹ Department of Surgery, MacKay Memorial Hospital, Taipei, Taiwan

¹² Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.

¹³ School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer, with the second highest mortality rate in all cancer. Energy reprogramming is one of the hallmarks of cancer, and emerging evidence showed that targeting glycolysis is a promising strategy for HCC treatment. Cryptocaryone has been shown to display promising anti-cancer activity against numerous types of cancer. Previous study also indicated that cryptocaryone induces cytotoxicity by inhibiting glucose transport in cancer cells, but the detailed mechanism still needs to be elucidated. Therefore, this study aimed to investigate the relationship between the anti-cancer effect and glycolytic metabolism of cryptocaryone in human HCC cells. In this study, we found that cryptocaryone potently induced growth inhibition by apoptotic cell death in HCC cells. Cryptocaryone also suppressed the ATP synthesis, lactate production and glycolytic capacity of HCC cells. Mechanistic investigations showed that phosphorylation of Akt and c-Src, as well as the expression of HK1 were impeded by cryptocaryone. Moreover, cryptocaryone markedly increased the expression level of transcription factor FoxO1. Importantly, clinical database analysis confirmed the negative correlation between HK1 and FoxO1. High expression levels of HK-1 were positively correlated with poorer survival in patients with HCCs. These results suggest that cryptocaryone may promote cell apoptosis by inhibiting FoxO1-mediated aerobic glycolysis through Akt and c-Src signaling cascades in human HCC cells. This is the first study to indicate that cryptocaryone exerts anti-cancer property against human HCC cells. Cryptocaryone is a potential natural product worthy of further development into a promising candidate for HCC treatment.

Keywords: Cryptocaryone, Hepatocellular carcinoma, Apoptosis, Glycolysis

https://doi.org/10.38212/2224-6614.3480