Emerging roles of non-coding RNAs in modulating the PI3K/Akt pathway in cancer

Abstract

Cancer progression results from the dysregulation of molecular pathways, each with unique features that can either promote or inhibit tumor growth. The complexity of carcinogenesis makes it challenging for researchers to target all pathways in cancer therapy, emphasizing the importance of focusing on specific pathways for targeted treatment. One such pathway is the PI3K/Akt pathway, which is often overexpressed in cancer. As tumor cells progress, the expression of PI3K/Akt increases, further driving cancer advancement. This study aims to explore how ncRNAs regulate the expression of PI3K/Akt. NcRNAs are found in both the cytoplasm and nucleus, and their functions vary depending on their location. They can bind to the promoters of PI3K or Akt, either reducing or increasing their expression, thus influencing tumorigenesis. The ncRNA/PI3K/Akt axis plays a crucial role in determining cell proliferation, metastasis, epithelial-mesenchymal transition (EMT), and even chemoresistance and radioresistance in human cancers. Anti-tumor compounds can target ncRNAs to modulate the PI3K/Akt axis. Moreover, ncRNAs can regulate the PI3K/Akt pathway both directly and indirectly.

Keywords: Cancer progression; Cancer therapy; Chemotherapy; Non-coding RNAs; PTEN; Radiotherapy.

Graphical abstract

Fig. 1

An overview of the PI3K/Akt/mTOR axis: PI3K can be activated by GPCRs, facilitating the conversion of PIP2 to PIP3. This conversion then activates the PDK1/Akt axis, which enhances mTOR levels. Subsequently, mTOR is translocated to the nucleus to regulate gene expression, impacting proliferation, metastasis, therapy resistance, and other mechanisms such as cell death and metabolism. PTEN can suppress the conversion of PIP2 to PIP3. Additionally, RTKs can activate the RAS/ERK axis, contributing to mTOR signaling activation.

Fig. 2

The role of miRNAs in regulating the PI3K/Akt pathway: miR-214 downregulates Netrin-1, activating the PI3K/Akt axis to enhance cisplatin resistance; miR-183 induces PTEN, downregulating the PI3K/Akt pathway to overcome drug resistance; miR-590-3p activates the PI3K/Akt axis, mediating radio-resistance; miR-501 downregulates BLID, inducing the PI3K/Akt pathway to mediate doxorubicin resistance; miR-1269b downregulates PTEN, activating the PI3K/Akt axis and triggering cisplatin resistance; miR-181c downregulates the PI3K/Akt pathway, mediating paclitaxel sensitivity.

Fig. 3

The regulation of PI3K/Akt by lncRNAs: MIR31HG activates the PI3K/Akt axis to enhance the progression of nasopharyngeal cancer; CCAT2 induces the PI3K/Akt pathway by sponging miR-216b; H19 stimulates the PI3K/Akt axis to enhance paclitaxel resistance; NORAD sponges miR-520a-3p, mediating the PI3K/Akt axis through PTEN downregulation; LINC00839-mediated PI3K/Akt activation promotes paclitaxel resistance; HOTAIR induces doxorubicin resistance by upregulating the PI3K/Akt axis.

Fig. 4

The regulation of PI3K/Akt by circRNAs in human cancers: Circ-0001313 sponges miR-510-5p to activate the PI3K/Akt axis; Circ-NRIP1 sponges miR-595 to upregulate SEMA4D, thereby inducing the PI3K/Akt axis; Circ-0006089 sponges miR-143-3p to upregulate the PI3K/Akt pathway; Circ-0000520 suppresses the PI3K/Akt axis to overcome Herceptin resistance; Circ-0007022 sponges miR-338-3p to mediate the PI3K/Akt axis; Circ-0000317 downregulates miR-494-3p to induce PTEN, leading to the suppression of the PI3K/Akt pathway.