PTEN defects in cancer, from gene to protein molecular causes and therapeutic targets

Abstract

Recently, cancer has become a leading cause of death worldwide, prompting increased research to understand the pathways involved in cancer development and to identify solutions for its treatment. The PI3K/AKT pathway has garnered significant attention because of its involvement in promoting cell proliferation and inhibiting programmed cell death. The protein phosphatase and tensin homolog on chromosome 10 (PTEN) plays a crucial role in inhibiting this pathway, thereby limiting uncontrolled cell proliferation. PTEN gene expression is strictly regulated at the transcriptional, posttranscriptional, and posttranslational levels, and recent research has focused on PTEN due to its reduced levels in cancer cells. This review aims to provide a deep understanding of the PTEN protein from structural and regulatory perspectives, its mutated forms, and its interactions with the occurrence of various malignant tumors to summarize the recent work performed to combat cancers via molecular strategies to enhance PTEN.

Keywords: LncRNA; MiRNA; PI3K/AKT pathway; PTEN; PTEN and cancer.

Fig. 1

PTEN protein structure. Section (A) shows the structure of the PTEN domain (the phosphatase domain is shown in blue, and the C2 structural domain is shown in red), and section (B) shows that PTEN consists of 403 amino acids, the three domains of PTEN, and the catalytic center

Fig. 2

The tumor suppressor PTEN attenuates PI3K/AKT signaling via PIP3-to-PIP2 conversion. Illustrates the mechanism by which the PI3K/AKT pathway is activated within the cell through a series of signals that begin with the binding of the ligand to the receptor tyrosine kinases and end with the activation of AKT, leading to tumor growth induction, and how PTEN intervenes to inhibit this pathway and counteract tumor development. This image was generated by drawing software to provide a brief overview of the PI3K/AKT pathway and the site of PTEN intervention

Fig. 3

Roles of PTENP1 transcripts in regulating PTEN levels. The regulatory functions of PTENP1 transcripts are distinct: PTENP1-AS-α suppresses PTEN expression by recruiting epigenetic modifiers to the promoter region, whereas PTENP1-AS-β stabilizes the PTENP1-S transcript through polyadenylation. This stabilization enables PTENP1-S to act as a competitive endogenous RNA (ceRNA), sequestering miRNAs and thereby safeguarding PTEN mRNA from degradation. Together, these mechanisms fine-tune PTEN levels through coordinated transcriptional and posttranscriptional regulation

Fig. 4

Mechanism of PTEN loss in various types of cancer with the highest and lowest rates. Inactivation of PTEN in cancer shows distinct patterns across tumor types. For example, through a protein promoter methylation mechanism, the highest percentage of lung cancer cases is 38% [45], and the lowest percentage of prostate cancer cases is 5% [46] (Sect. 1). Mutations are highest in endometrial cancer (41%) [47] and lowest in breast cancer (3%) [48] (Sect. 2). On the other hand, glioblastoma has the highest percentage of protein deletions, at 78% [49], whereas colorectal cancer has the lowest percentage according to the previous mechanism, at a rate of 8.7% [50] (Sect. 3). Finally, through the protein loss mechanism, we find that glioblastoma accounts for the highest percentage at 65% [51], whereas colorectal [50] and breast cancer [45] account for the lowest percentage at 40% (Sect. 4). These tumor-specific variations highlight the diverse molecular mechanisms underlying PTEN pathway disruption in different malignancies

Fig. 5

PTEN-Targeting miRNAs in multilineage carcinogenesis. Illustrates the presence of various types of miRNAs in different types of cancers and their mechanism in promoting tumor progression by inhibiting PTEN and enhancing the PI3K/AKT pathway

Fig. 6

miRNAs cause chemotherapy resistance according to tumor cell origin. Illustrates one of the mechanisms by which miRNAs enhance tumor growth by rendering cancer cells resistant to various drugs that inhibit tumor development

Fig. 7

LncRNA types. Illustrates the lncRNAs presented in the previous table, which are classified into two functional groups: tumor inhibitors and tumor stimulators

Fig. 8

Therapeutic PTEN restoration: CRISPR technology, mRNA delivery and miRNA modulation. Illustrates therapeutic strategies to increase PTEN levels in PTEN-deficient cells, including gene targeting via CRISPR technology, vesicle-mediated delivery of PTEN mRNA or modulation of PTEN-targeting miRNA via delivery of PTENP1 or LncRNA