Page 48 - ARNM-3-3

Advances in Radiotherapy
& Nuclear Medicine PI3K and Akt in androgen-independent PCa

in poorly differentiated PCa and lower in moderately and direct relationship between the mTOR and AR signaling
well-differentiated PCa. A positive correlation has also been pathways, revealing a dynamic interaction contributing
observed between Akt expression and PCa prognosis. to the development of androgen insensitivity. 19,20 The
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These findings suggest that AR activation is associated with PI3K/Akt/mTOR signaling pathway is frequently activated
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the Akt signaling pathway, and the interaction between in a variety of cancers, including PCa. Liang et al. 22
AR and the Akt signaling pathway may contribute to the reported that G protein-coupled receptor 48/leucine-
transition to androgen independence and may be closely rich repeat-containing G-protein coupled receptor 4
related to the onset and progression of adenocarcinoma. promotes PCa progression by activating the PI3K/Akt
pathway. Conversely, inhibition of the PI3K/Akt signaling
In this study, based on the diagnostic criteria for AIPC,
an equal number of patients (n = 38/group) from the AIPC by upregulated tumor necrosis factor-a (TNF-a)-induced
protein 8-like 2 (TIPE2) suppresses invasion, proliferation,
and ADPC patient groups were assessed for AR, PI3K, and migration of PCa cells. Furthermore, PI3K/Akt
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and Akt expression through immunolabeling. To explore signaling can substitute for androgen function following
whether differences exist between AIPC and ADPC, this androgen deprivation, thereby promoting cancer growth.
study assessed the expression profiles of AR, PI3K, and
Akt in paraffin-embedded tissue, as well as the correlations In the present study involving 76 patients, although the
among AR, PI3K, and Akt in AIPC. expression rates of PI3K and Akt reached 100% in both
groups, the expression in AIPC was significantly higher
According to the GS, notably, 100% of AIPC tumors than in ADPC, with the difference being statistically
were classified as high-risk (GS > 7), comprising grade significant (p < 0.001). The elevated expression in AIPC
group 4 (GS = 8; 71.1%; 27/38) and grade group 5 may compensate for androgen loss to sustain tumor
(GS = 9 – 10; 28.9%; 11/38). In contrast, ADPC tumors growth, indicating that AIPC formation may be closely
were distributed across the five GS grade groups: grade associated with the PI3K/Akt pathway. Spearman’s
group 1 (GS = 6; 18.4%), grade group 2 (GS = 7; 28.9%), analysis reveals a positive correlation between AR and
grade group 3 (GS = 7 [4 + 3]; 18.4%), grade group 4 Akt expression in AIPC. The PI3K/Akt signaling pathway
(GS = 8; 18.4%), and grade group 5 (GS = 9 – 10; 20.1%). plays a critical role during the progression from ADPC to
Correlation analysis shows that the GS values of the AIPC AIPC, showing a strong association with PCa progression.
cohort are significantly higher than those of the ADPC Therefore, PI3K expression may serve as an important
group, consistent with their substantially poorer prognosis. biomarker for clinical staging and prognosis evaluation in
To date, ADT remains the primary treatment for PCa.
advanced PCa. The growth of most PCa is androgen- The interaction between AR and Akt plays a crucial
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dependent and highly sensitive to ADT. 15,16 However, role in the onset and progression of AIPC. This study
despite achieving castration levels of serum testosterone, shows that the synergistic effect of AR and Akt is a key
tumor growth often persists. One of the most important factor in the transformation of prostate epithelial cells into
mechanisms driving castration resistance is sustained AIPC. Studies have shown that AR expression, stability,
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activation of AR signaling. 16 and transcriptional activity are regulated through the
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Previous studies have reported that most PCa cases PI3K/Akt signaling pathway. Manin et al. found that
express AR throughout the course of disease progression. activated Akt enhances the expression of AR, indicating a
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Consistent with these findings, this study observed a 100% positive correlation between the two. Sharma et al. further
AR expression rate in both the ADPC (n = 38) and AIPC demonstrated that Akt modulates the interaction between
(n = 38) patient groups. Bypass activation of the AR was AR and its coactivator, β-catenin. Increased β-catenin
observed. This activation was not dependent on hormones, binds to AR, enhances its transcriptional activity, and
suggesting that factors mimicking androgen activity after contributes to PCa progression.
castration may continue to activate AR. The abnormal In the present study, the expression of AR and PI3K,
reactivation of the AR signaling axis remains crucial in the as well as AR and Akt, in AIPC was found to be positively
progression of this fatal disease. correlated, suggesting that a potential relationship may

Studies have reported that compensatory activation exist between AR and PI3K expression, and between AR
through signal transduction pathways is another important and Akt expression, respectively. Moreover, the expression
mechanism driving the development of castration-resistant levels of PI3K and Akt in AIPC patients were also positively
PCa. The PI3K/Akt signaling pathway represents one correlated.
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such mechanism. The PI3K pathway loses regulatory The PI3K/Akt signaling pathway plays an important role
control in PCa. Recent studies have demonstrated a in the transformation of ADPC to AIPC and is positively
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Volume 3 Issue 3 (2025) 40 doi: 10.36922/ARNM025160018