RSK4 inhibition results in bypass of stress-induced and oncogene-induced senescence

Abstract

p90 Ribosomal S6 kinase (RSK) 4 is a serine-threonine kinase that belongs to the p90RSK family. RSK4 has been proposed as a tumor suppressor gene, related with anti-invasive activity, inhibition of the RAS-mitogen-activated protein kinase (MAPK) pathway and induction of senescence. Despite the related findings, little is known about RSK4 effectors. In human tumors, RSK4 is downregulated even in some benign lesions, such as colon adenomas and breast papillomas, indicating that RSK4 inhibition could be an early event in cellular transformation. For cells to achieve immortality and transformation, it is believed that they must override senescence. In the present study, we found that when RSK4 is inhibited in vitro using short hairpin RNA technology, cells can bypass stress-induced senescence and oncogene-induced senescence: normal human fibroblasts grew following oxidative stress, induction of DNA damage and KRAS(V12) or BRAF(E600) overexpression. To investigate the RSK4 effectors, we used short hairpin RNA or inhibitor molecules against major senescence mediators. We found that RSK4-induced senescence is mediated through p21, but is independent of p16, p38MAPKs and induction of reactive oxygen species, delimiting RSK4 signaling. These data support the importance of RSK4 for regulating senescence and indicate that downregulation of this kinase could be an important element in facilitating cell transformation.

RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer

“…RSKs are directly regulated by ERK signaling and are implicated in cell growth, survival, motility, and senescence (25)(26)(27)(28). Here, we present evidence that overexpression of RSK3 and RSK4 supports cellular proliferation under PI3K pathway blockade by inhibiting apoptosis and regulating cellular translation through phosphorylation of ribosomal proteins S6 and eIF4B.…”

“…RSK1 and RSK2 have been reported as overexpressed in breast and prostate cancer, while RSK3 has been proposed to be a tumor suppressor in ovarian cancer (55)(56)(57). RSK4 has previously been characterized as essential for p53-dependent proliferation arrest as well as stress-and oncogene-induced senescence (28,58,59). Interestingly, the RSK4 isoform exhibits constitutively high activity, is upregulated in MMTV-Myc mouse breast tumors, is aberrantly expressed in breast cancer, and has been implicated in sunitinib resistance (58,(60)(61)(62)(63).…”

The p90 RSK Family Members: Common Functions and Isoform Specificity

“…Indeed, in breast cancer cells, overexpression of RSK4 leads to G 0 /G 1 cell-cycle arrest whereas inhibition of RSK4 results in a bypass of stress-and oncogene-induced senescence (28). However, in the lung, our own data suggest that, while undetectable in normal epithelium, RSK4 is overexpressed in more than 50% of primary malignant lesions (3), suggesting that RSK4 may provide tumor cells with a growth advantage.…”

“…In contrast, several reports suggest that RSK4 behaves as a tumor suppressor the expression of which is downregulated in human tumors (28). Indeed, in breast cancer cells, overexpression of RSK4 leads to G 0 /G 1 cell-cycle arrest whereas inhibition of RSK4 results in a bypass of stress-and oncogene-induced senescence (28).…”

RPS6KA6 (Ribosomal Protein S6 Kinase, 90kDa, Polypeptide 6)

“…Also, inhibition of RSK4 causes bypass of cellular senescence induced by stress or oncogene, suggesting RSK4 inhibition may be an important factor in facilitating cell transformation. (López-Vicente et al, 2011). shRNA against RPS6KA6 bypassed p53-dependent G1 cell cycle arrest and suppressed mRNA expression of cyclin-dependent kinase inhibitor p21 cip1 , suggesting RSK4 is needed for growth arrest induced by p53 (Berns et al, 2004).…”