Lysosomal alkalinization in nutrient restricted cancer cells activates cytoskeletal rearrangement to enhance partial epithelial to mesenchymal transition

Date

2024-03-01

Author

Hüsnügil, Hepşen Hazal
Güleç Taşkıran, Aliye Ezgi
Güderer, İsmail
Nehri, Leman Nur
Oral, Göksu
Menemenli, Nazlı Şevval
Özcan, Özün
Noghreh, Ariana
AKYOL, AYTEKİN
Banerjee, Sreeparna

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Introduction: Nutrient restriction in cancer cells can activate a number of stress response pathways for cell survival. We aimed to determine mechanistically how nutrient depletion in colorectal cancer (CRC) cells leads to cellular adaptation. Materials and methods: Cell survival under nutrient depletion (ND) was evaluated by colony formation and in vivo tumor formation assays. Lysosomes are activated with ND; therefore, we incubated the ND cells with the V-ATPase inhibitor Bafilomycin A1 (ND+Baf). The expression of epithelial and mesenchymal markers with ND+Baf was determined by RNA sequencing and RT-qPCR while motility was determined with an in vivo Chorioallantoic membrane (CAM) assay. Reorganization of cytoskeletal network and lysosomal positioning was determined by immunocytochemistry. Results: 4 different colorectal cancer (CRC) cell lines under ND showed high viability, tumor forming ability and increased expression of one or more epithelial and mesenchymal markers, suggesting the activation of partial (p)-EMT. We observed a further increase in p-EMT markers, numerous membrane protrusions, decreased cell-cell adhesion in 3D, and increased motility in ND+Baf cells. The protrusions in the ND+Baf cells were primarily mediated by microtubules and enabled the relocalization of lysosomes from the perinuclear region to the periphery. Conclusions: ND activated p-EMT in CRC cells, which was exacerbated by lysosomal alkalinization. The ND+Baf cells also showed numerous protrusions containing lysosomes, which may lead to lysosomal exocytosis and enhanced motility.

Subject Keywords

Lysosome, cytoskeleton, Nutrient restriction, Partial EMT

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https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85183138093&origin=inward
https://hdl.handle.net/11511/108602

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Department of Biology, Article