The complex role of GOLPH3 in chemoresistance
Il 08/05/2025 ore 14.30 - 17.00
Via Pietro Castellino n. 111 Napoli c/o Area di Ricerca Napoli 1
Seminar at the Cnr Institute of Biochemistry and Cell Biology, held by dr. Domenico Russo (Cnr Institute of Endoypes in Oncology, Metabolism and Immunology "Gaetano Salvatore")
Abstract
Sphingolipids (SLs) encompass various bioactive lipids with roles ranging from cytostatic and proapoptotic to growth-promoting. The intricate balance between these species is crucial for cellular fate determination and stress response, governed by control systems regulating their production and intracellular movement, notably at the trans-Golgi network (TGN), where
sphingomyelin production is finely tuned.
Ceramide, a pivotal SL, is ferried from the endoplasmic reticulum (ER) to the TGN via non vesicular transport mediated by CERT. At the TGN, ceramide is converted to sphingomyelin by SMS1, yielding diacylglycerol as a byproduct. Locally produced diacylglycerol activates protein kinase D (PKD), which phosphorylates and deactivates CERT, halting sphingomyelin synthesis. PKD
activation also affects phosphoinositide turnover at the TGN, disrupting lipid exchange between the ER and Golgi.
Consequently, increased ceramide levels inhibit its transport out of the ER, crucial for cell fate as unchecked ceramide promotes cell cycle arrest and apoptosis. Disposal of ER-located ceramide involves conversion to glycosylated derivatives, particularly glycosphingolipids (GSLs), which possess growth-promoting properties. This led to an inquiry into how the ceramide glycosylating machinery reacts to excess sphingolipid flux.
The Golgi oncoprotein GOLPH3 functions facilitating retrograde transport of GLSs synthesizing enzymes to the ER, intercepting and disposing of the ceramide pool. Our findings demonstrate that the sphingolipid overload activates PKD which culminates in GOLPH3 phosphorylation on Ser124 amino acid residue. Gene copy number variation and protein overexpression of GOLPH3 in several solid tumors underline the crucial role of GOLPH3 phosphorylation in preventing apoptosis triggered by ceramide accumulation. Given that the anti-cancer treatment approaches like Chemotherapy/Radiotherapy aim to accumulate ceramide, GOLPH3 amplification could not only make ineffective the attempt at ceramide- induced apoptosis, and chemoresistance phenomenon, but could represent
fuel for the continuous production of GSLs which contributes to activate survival/proliferation pathways in tumor cells.
By combining biochemistry, live cell imaging (2D and 3D), and OMIC tools we are shedding light on the molecular basis of the chemoresistance in tumors with altered genetic background of GOLPH3 to prove how GOLPH3 could represent a valid pharmacological target.
Organizzato da:
Istituto di biochimica e biologia cellulare (Cnr-Ibbc)
Referente organizzativo:
Maria Trovato
Cnr-Ibbc
Via Pietro Castellino n. 111 Napoli
maria.trovato@cnr.it
Modalità di accesso: ingresso libero
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