Abstract
For many tumor types chemotherapy still represents the therapy of choice and many standard treatments are based on the use of platinum (PT) drugs. However, de novo or acquired resistance to platinum is frequent and leads to disease progression. In Epithelial Ovarian Cancer (EOC) patients, PT-resistant recurrences are very common and improving the response to treatment still represents an unmet clinical need. To identify new modulators of PT-sensitivity, we performed a loss-of-function screening targeting 680 genes potentially involved in the response of EOC cells to platinum. We found that SGK2 (Serum-and Glucocorticoid-inducible kinase 2) plays a key role in PT-response. We show here that EOC cells relay on the induction of autophagy to escape PT-induced death and that SGK2 inhibition increases PT sensitivity inducing a block in the autophagy cascade due to the impairment of lysosomal acidification. Mechanistically we demonstrate that SGK2 controls autophagy in a kinase-dependent manner by binding and inhibiting the V-ATPase proton pump. Accordingly, SGK2 phosphorylates the subunit V1H (ATP6V1H) of V-ATPase and silencing or chemical inhibition of SGK2, affects the normal autophagic flux and sensitizes EOC cells to platinum. Hence, we identified a new pathway that links autophagy to the survival of cancer cells under platinum treatment in which the druggable kinase SGK2 plays a central role. Our data suggest that blocking autophagy via SGK2 inhibition could represent a novel therapeutic strategy to improve patients’ response to platinum.
Highlights
These authors contributed : Valentina Ranzuglia, Ilaria Lorenzon, and Ilenia PellarinThese authors jointly supervised this work: Gustavo Baldassarre and Monica Schiappacassi
To unveil key genes involved in the regulation of PT sensitivity of Epithelial Ovarian Cancer (EOC) cells we used a functional genomic approach targeting 680 genes related to apoptosis, p53 and
To understand how SGK2 regulates the PT-sensitivity in EOC cells, we first investigated if its kinase activity was involved
Summary
These authors contributed : Valentina Ranzuglia, Ilaria Lorenzon, and Ilenia Pellarin. We performed a loss-of function screening to identify genes able to impact on PT treatment targeting the pathways linked to PT-resistance in EOC. Using this approach, we unveiled SGK2, serum-and glucocorticoid- kinase 2, as a novel modulator of platinum sensitivity. Among the confirmed ones [33, 34] (described, Data File S1), SGK2 silencing showed increased PT-induced death in three out of four different EOC cell lines used (i.e., MDAH, OV90 and SKOV3 but not in TOV112D) (Fig. S1b). Given the high sequence homology described for the three members of the SGK family [24, 35] we analyzed the expression of SGK1 and SGK3 in normal and cancer-derived EOC cells and tested if their silencing could have any role in PT-sensitivity. Using MDAH as a model, we observed that silencing of SGK3 and SGK1 was specific and did not affect their survival and the PT-sensitivity (Fig. S2b, c)
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