Arthur Murtaugh

Background: Hepatocellular carcinoma is one of the most common causes of cancer worldwide and comprises around 90% of all liver cancers. The PI3K/AKT/mTOR growth pathway has been implicated in other cancers and is thought to drive Hepatocellular carcinoma (HCC) progression. The phosphorylation of PI3K will lead to a downstream kinase cascade, which promotes cell growth, inhibition of cellular apoptosis and autophagy, and increased glucose and nutrient metabolism. High levels of SNRPD1, PDK1, and SOCS5 could play a potential role in the pathogenesis of HCC by inhibiting autophagy and promoting treatment resistance. The induction and restoration of autophagy could serve as a potential treatment mechanism. Together, these treatments could point to a new strategy for targeting HCC.

Objective: In this narrative review, we explore the mechanism by which the PI3K/AKT/mTOR pathway and autophagy are dysregulated in Hepatocellular carcinoma and how the induction of autophagy may lead to several potential therapeutic targets.

Search Methods: A PubMed search using “Hepatocellular carcinoma”, “Autophagy”, and “PI3K/AKT/mTOR” was done. The date range for these references was from 2019 and onwards.

Results: SNRDP1 upregulation was associated with worse clinical prognosis, tumor size, metastasis, and survival rates ^{1, 2} . Knockdown of SNRPD1 showed much lower levels of cell migration, invasion, and proliferation compared to the control and empty vector.¹ Knockdown of SNRPD1 showed around 5-6 autophagosomes compared to 1.8-2 in control cells.¹ Western blotting showed markedly reduced downstream activation of PI3K phosphorylation in knockdown cells compared to normal. Transfection into nude mice showed a decrease in tumor size in knockout mice. SOCS5 was overexpressed in HCC tissues.³ Overexpression of SOCS5 enhanced cell migration and invasion and was associated with higher levels of p-PI3K, p-AKT, and p-mTOR, while knockdown of SOCS5 increased autophagic markers LC3 and Beclin-1.³ The anti-metastatic effects of SOCS5 inhibition were reversed by treatment with the autophagy inhibitor 3-MA, confirming an autophagy-mediated mechanism.³ Overexpression of PDK1, a downstream effector of PI3K, correlated with radiation-resistant phenotypes.⁴ siPDK1 was able to restore radiation sensitivity and suppress PI3K/AKT/mTOR signaling.⁴ Treatment of cells with Piezoelectric Cold Atmospheric plasma was able to induce autophagy and apoptosis in HCC cells.⁵ Piezo-CAP treatment led to decreased cell size, reduction in oncogenesis, increase in autophagic and apoptotic markers, and an inhibition of downstream activation of the PI3K/AKT pathway.⁵

Conclusions: The PI3K/AKT/mTOR pathway has been shown to promote tumorigenesis, which leads to worse patient outcomes and increased treatment resistance. Targeting proteins such as SNRPD1 and SOCS5 that lead to the induction of autophagy and reduction in cell migration, invasion, and proliferation could serve as potential therapies for hepatocellular carcinoma. Knockdown of SNRPD1 and SOCS5 restored autophagy and increased pro-autophagic proteins such as LC3 and Beclin-1. This greatly reduces phosphorylated PI3K, AKT, and mTOR levels. Aberrant PDK1 expression was shown to be correlated with treatment resistance and further upregulate the PI3K/AKT/mTOR pathway. Inhibition of PDK1 may serve as a potential therapeutic target to co-administer with ionizing radiation in HCC therapy. If these therapies are ineffective, Piezo-CAP may be an alternative option that can be used to induce apoptosis and autophagy. Piezo-CAP’s ability to suppress PI3K/AKT/mTOR signaling and decrease migration and invasion makes it a potential therapy for HCC.

1. Works Cited:
2. Wang H, Chen M, Yang C, et al. SNRPD1 inhibition suppresses the proliferation of hepatocellular carcinoma and promotes autophagy through the PI3K/AKT/mTOR/4EBP1 pathway. Archives of Biochemistry and Biophysics. 2023;743:109661. doi:https://doi.org/10.1016/j.abb.2023.109661
3. Wang H, Xu F, Lu L, et al. The diagnostic and prognostic significance of small nuclear ribonucleoprotein Sm D1 aberrantly high expression in hepatocellular carcinoma. Journal of Cancer. 2021;13(1):184-201. doi:https://doi.org/10.7150/jca.65225
4. Zhang M, Liu S, Chua MS, et al. SOCS5 inhibition induces autophagy to impair metastasis in hepatocellular carcinoma cells via the PI3K/Akt/mTOR pathway. Cell Death and Disease. 2019;10(8). doi:https://doi.org/10.1038/s41419-019-1856-y
5. Bamodu OA, Chang HL, Ong JR, Lee WH, Yeh CT, Tsai JT. Elevated PDK1 Expression Drives PI3K/AKT/MTOR Signaling, Promotes Radiation-Resistant and Dedifferentiated Phenotype of Hepatocellular Carcinoma. Cells. 2020;9(3):746. doi:https://doi.org/10.3390/cells9030746
6.  Wang Y, Mang X, Li D, Chen Y, Cai Z, Tan F. Piezoeletric cold atmospheric plasma induces apoptosis and autophagy in human hepatocellular carcinoma cells through blocking glycolysis and AKT/mTOR/HIF-1α pathway. Free radical biology & medicine. 2023;208:134-152. doi:https://doi.org/10.1016/j.freeradbiomed.2023.07.036
7. Ganne-Carrié, N., & Nahon, P. (2019). Hepatocellular carcinoma in the setting of alcohol-related liver disease. Journal of Hepatology, 70(2), 284–293. https://doi.org/10.1016/j.jhep.2018.10.008
8. Yang, J. D., Hainaut, P., Gores, G. J., Amadou, A., Plymoth, A., & Roberts, L. R. (2019). A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nature Reviews Gastroenterology & Hepatology, 16(10), 589–604. https://doi.org/10.1038/s41575-019-0186-y
9. Kouroumalis, E., Ioannis Tsomidis, & Argyro Voumvouraki. (2023). Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy. Biomedicines, 11(4), 1166–1166. https://doi.org/10.3390/biomedicines11041166