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INTERNATIONAL CONGRESS OF

PharmacoGenetics

• PI3K/AKT/mTOR signaling pathway and the influence of miRNAs in cancer

• Yasaman Baharvand ,¹ Mohammad Shafiei,^2,* Mozhdeh Hosseini,³
  1. Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
  2. Department of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz
  3. Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
  
  
  
• Introduction: Cancer development is driven by genomic mutations that promote abnormal proliferation, along with mechanisms of immune evasion. Research has focused on identifying oncogenic drivers in tumors, including phosphoinositide 3‐kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), RAS/MAPK, and MYC pathways (1). The PI3K/AKT/mTOR pathway is often overstimulated in cancer cells resistant to chemotherapy, radiation, and hormone therapy (2). Similarly, the PI3K/PTEN/AKT/mTOR tumor suppressor pathway is frequently impaired, with its components inactivated by deletion, silencing, or mutation (3). The PI3K/AKT/mTOR signaling axis plays a central role in cancer progression by regulating cell growth, survival, and metabolism. Hyperactivation is commonly caused by mutations or loss of tumor suppressors such as PTEN that enhances proliferation, inhibits apoptosis, and activates mTOR, which drives protein synthesis and suppresses autophagy. This pathway also supports therapy resistance, immune evasion, and metastasis. While targeting PI3K, AKT, or mTOR with inhibitors holds therapeutic promise, resistance to these agents remains a significant challenge (1). The PI3K/AKT/mTOR pathway plays crucial roles in multiple diseases and cancer progression, influencing apoptosis, autophagy, and survival in many cancer types. The GENEOM study reported that single nucleotide polymorphisms (SNPs) in this pathway are linked to distant metastasis. It promotes cell survival by inhibiting apoptosis-related genes such as BAD, BAX, caspase-9, GSK-3, and FOXO1, while upregulating anti-apoptotic proteins like NF-κB and CREB. As a major negative regulator of autophagy, pathway activation via mTOR suppresses ULK1 complex activity, reducing autophagy. mTOR inhibition, however, induces autophagy by increasing LC3-II, ATG3, and ATG5, and decreasing p62. Additionally, PI3K/AKT signaling drives chemoresistance and supports epithelial–mesenchymal transition (EMT) in drug-resistant, metastatic cancer cells. Additionally, PI3K/AKT signaling is of crucial importance for chemoresistance, and contributes to epithelial-mesenchymal transition (EMT) which occurs in drug-resistant and metastatic human cancer cells (4) Dysregulation of the AKT/mTOR pathway occurs in several malignancies, promoting tumor progression and treatment resistance. miRNAs are small, non-coding RNAs that regulate gene expression at the post-transcriptional level by targeting messenger RNAs (mRNAs) for degradation or translational repression. miRNAs can directly target AKT/mTOR pathway components, influencing oncogenesis. Aberrant miRNA expression often correlates with tumor stage, lymph node involvement, and patient survival (5).
• Methods: We searched databases like PubMed and Google Scholar using keywords such as “PI3K/AKT/mTOR,” “miRNA,” and “cancer.” Our focused was on papers published from 2020 to 2025 and picked the most relevant ones that talked about how this pathway and miRNAs affect cancer.
• Results: miRNAs are short, non-coding RNA molecules, generally about 22 nucleotides in length, that are highly conserved and naturally encoded in the genomes of many species (6). These transcripts are not translated into proteins but instead regulate gene expression at the post-transcriptional level. miRNA genes can be located within introns or exons of protein-coding genes, as well as in intergenic regions, which are often unstable (7). miRNAs can influence all hallmarks of cancer, acting either as tumor suppressors or as promoters of oncogenic processes (8). With the advancement of next-generation sequencing (NGS) and microarray technologies, various miRNAs have been identified as regulators of the Akt/mTOR pathway. Among these, miR-21, miR-29, miR-99, and miR-100 are notable modulators of this signaling cascade (5). Increased expression of miR-21 can suppress several tumor-related target genes, including SPRY2, PTEN, RECK, TIMP3, BCL2, and PDCD4. SPRY2 functions as a negative regulator of both the PI3K/AKT/mTOR and ERK/MAPK pathways by influencing the endosomal trafficking of EGFR and HER2, as well as by inhibiting Raf1. When SPRY2 is absent, cell proliferation becomes uncontrolled, although angiogenesis is reduced. PTEN, another direct target of miR-21, inhibits AKT activation and thereby restrains PI3K/AKT/mTOR pathway activity. Loss of PTEN allows AKT to activate mTORC1 through phosphorylation and inactivation of TSC2 or phosphorylation of PRAS40, leading to enhanced cell growth, proliferation, survival, and motility (9).
• Conclusion: The PI3K/AKT/mTOR pathway is one of the most frequently dysregulated pathway in cancer, driving initiation, progression, metastasis, and therapy resistance. Aberrant activation enhances proliferation, survival, and metabolism. miRNAs act as crucial modulators, functioning as oncogenes or tumor suppressors by regulating components like PTEN, AKT, and mTOR. Combining miRNA-based strategies with PI3K/AKT/mTOR inhibitors holds strong potential to overcome resistance, improve outcomes, and extend patient survival.
• Keywords: Cancer/ PI3K/AKT/mTOR/ signaling/ miRNA