Upregulation of LKB1-AMPK signalling pathway in sparsely granulated somatotropinomas: a phosphoproteomics based approach

Vaishali Kaur; Debajyoti Chatterjee; Apinderpreet Singh; Sivashanmugam Dhandapani; Soham Mukherjee; Sandeep Mohindra; Ansh Sukhija; Dibyajyoti Banerjee; Ashutosh Rai; Pinaki Dutta

doi:10.1530/endoabs.109.P198

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Endocrine Abstracts (2025) 109 P198 | DOI: 10.1530/endoabs.109.P198

SFEBES2025 Poster Presentations Neuroendocrinology and Pituitary (48 abstracts)

Upregulation of LKB1-AMPK signalling pathway in sparsely granulated somatotropinomas: a phosphoproteomics based approach

Vaishali Kaur ¹ , Debajyoti Chatterjee ¹ , Apinderpreet Singh ¹ , Sivashanmugam Dhandapani ¹ , Soham Mukherjee ¹ , Sandeep Mohindra ¹ , Ansh Sukhija ² , Dibyajyoti Banerjee ¹ , Ashutosh Rai ² & Pinaki Dutta ¹

Author affiliations

¹PGIMER, Chandigarh, India; ²Panjab University, Chandigarh, India

Background: Based on granularity somatotropinomas are divided into sparsely (SG) and densely granulated (DG). SG shows aggressive clinical behaviour (presentation at a young age, with increased invasiveness, recurrence, and resistance to treatments as compared to DG. Upregulation of LKB1-AMPK pathway can support tumour survival and growth by promoting autophagy and providing an adaptive response to a nutrient-poor microenvironment.

Method: Quantitative mass spectrometry-based phosphoproteomics analysis was performed on SG (n = 4) and DG (n = 4) tumours. Candidates of significantly enriched pathways (cut-off=1.5 fold-change) were considered for validation by immunohistochemistry (IHC) (n = 10; SG=4, DG=6) on tissue microarray in a separate group of samples.

Results and Discussion: Mass spectrometry analysis revealed significant over-phosphorylation of 85 proteins belonging to the LKB1-AMPK pathway (fold enrichment = 1.8, P = 2.2E-09) in SG tumours. Antibody availability guided the selection of four candidates TSC1 Ser1080, AMPKβ Ser108, MAPT Thr548, and ULK1 Ser638 for IHC. Over-phosphorylation of AMPKβ Ser108 (6.0-fold, P = 0.0073) signifies AMPK activation, suggesting metabolic adaptation to energy stress. A substantial increase in TSC1 Ser1080 phosphorylation (9.5-fold, P = 0.01) implies inhibition of the TSC complex, potentially activating mTOR signalling and promoting anabolic processes in SG tumours. Over-phosphorylation of MAPT at Thr548 (3.8-fold, P = 0.02) suggests enhanced cytoskeletal dynamics, potentially facilitating invasion. Although ULK1 Ser638 phosphorylation showed a smaller, nonsignificant increase (1.8-fold, P = 0.54), this trend may indicate autophagic adaptation to metabolic stress. Upstream analysis identified PRKAA1 and GSK3β as regulators of AMPKβ Ser108 and MAPT Thr548, respectively, while mTOR phosphorylates TSC1 Ser1080 and ULK1 Ser638. IHC confirmed increase in mTOR expression in SG tumours (3.5-fold P = 0.01) compared to DG, underscoring mTOR’s role in driving tumour growth.

Conclusions: In SG tumours, PRKAA1-mediated AMPK activation, GSK3β-driven cytoskeletal remodelling and mTOR signalling, collectively promote tumour cell survival, growth and invasiveness.