Phosphoinositide 3-kinase inhibitors are effective therapeutic drugs for the treatment of hepatocellular carcinoma?

Article information

Clin Mol Hepatol. 2020;26(4):577-578

Publication date (electronic) : 2020 September 17

doi : https://doi.org/10.3350/cmh.2020.0143

Jeong Su Park, Soo Han Bae

Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea

Corresponding author : Soo Han Bae Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea Tel: +82-2 2228-0756, Fax: +82-2-2227-8129 E-mail: soohanbae@yuhs.ac

Editor: Jong-Hoon Kim, Korea University College of Medicine, Korea

Received 2020 June 30; Revised 2020 July 13; Accepted 2020 July 13.

Dear Editor,

Recently, we read an article entitled “Inhibition of PI3K/Akt signaling suppresses epithelial-to-mesenchymal transition in hepatocellular carcinoma through the Snail/GSK-3/beta-catenin pathway” by Lee et al. [1] with profound interest. The study showed that phosphoinositide 3-kinase (PI3K) inhibitors, LY294002 and Idelalisib, restrict epithelial-to-mesenchymal transition as indicated by upregulation of E-cadherin and downregulation of N-cadherin. Furthermore, PI3K inhibitors were reported to induce nuclear translocation of GSK-3β that was shown to decrease the expression of Snail and β-catenin in HepG2 and Huh-BAT cells. Subsequently, PI3K inhibitors were reported to supress the proliferation and invasion of hepatocellular carcinoma (HCC). However, before interpreting the results of the published study, several concerns should be taken into consideration.

At first, class I PI3K signaling has been known to be crucial for HCC progression, and thereby, substitutes as a therapeutic target for the treatment of HCC. Furthermore, PI3K has three catalytic subunits, which includes PI3K-α, PI3K-β, PI3K-δ [2]. Several studies have reported that upregulation of PI3Kδ is positively correlated with progression of human advanced cancers such as HCC and melanoma [3,4]. Moreover, Idelalisib is well-known as a first-in-class PI3Kδ inhibitor for the treatment of leukemia [5]. Recently, it has been reported that Idelalisib suppresses HCC progression [4]. Subsequently, high expression levels of PI3Kδ have been associated with advanced HCC [4]. However, PI3Kδ expression levels in Huh7-BAT and HepG2 cell lines have not been shown in this study. It is crucial to elucidate the effects of PI3Kδ inhibitor on HCC progression.

Secondly, it is well-known that LY294002 inhibits PI3K/AKT/mammalian target of rapamycin complex 1 (mTORC1) pathway [6]. In several cancers, this has been reported to cause significant reduction in the capability of cancer cells pertaining to viability, migration, and invasion [7,8]. However, AKT phosphorlation has been shown to be upregulated in LY294002-treated Huh-BAT cells. Thus, attributes of Huh-BAT cells need to be elucidated. Furthermore, the detailed mechanisms of LY294002 that lead to inhibition of PI3K/AKT/mTORC1 pathway in HCC cell lines are not yet evident. Subsequently, the mechanism needs to be further validated.

Furthermore, diverse roles of serine/threonine kinase glycogen synthase kinase 3 (GSK3β) in cancer progression still remain controversial [6]. However, several studies have reported that GSK3β acts as a tumor suppressor gene, and thereby, it has been suggested to be a promising therapeutic target for HCC treatment [9-11]. Additionally, GSK3β has been associated with signaling pathways such as Notch-, Wnt/β-catenin-, and transforming growth factor (TGF) β-pathway, that have been implicated in HCC pathogenesis [12]. However, the detailed interactive mechanisms of GSK3β and PI3K inhibitors are not elucidated. This study showed that PI3K inhibitors upregulate the expression of nuclear GSK3β, which further suppresses snail expression in liver cancer cell lines.

In conclusion, Lee et al.’s study [1] provides the anti-cancer effects and comprehensive mechanisms of PI3K inhibitors in HCC cell lines. It suggests that PI3K is a potential therapeutic target for the treatment of HCC.