Discrepancy Between Low Levels of mTOR Activity and High Levels of P-S6 in Primary Central Nervous System Lymphoma May Be Explained by PAS Domain-Containing Serine/Threonine-Protein Kinase-Mediated Phosphorylation

Abstract

The primary aim of this study was to determine mTOR-pathway activity in primary central nervous system lymphoma (PCNSL), which could be a potential target for therapy. After demonstrating that p-S6 positivity largely exceeded mTOR activity, we aimed to identify other pathways that may lead to S6 phosphorylation. We measured mTOR activity with immunohistochemistry for p-mTOR and its downstream effectors p(T389)-p70S6K1, p-S6, and p-4E-BP1 in 31 cases of PCNSL and 51 cases of systemic diffuse large B-cell lymphoma (DLBCL) and evaluated alternative S6 phosphorylation pathways with p-RSK, p(T229)-p70S6K1, and PASK antibodies. Finally, we examined the impact of PASK inhibition on S6 phosphorylation on BHD1 cell line. mTOR-pathway activity was significantly less frequent in PCNSL compared with DLBCL. p-S6 positivity was related to mTOR-pathway in DLBCL, but not in PCNSL. Among the other kinases potentially responsible for S6 phosphorylation, PASK proved to be positive in all cases of PCNSL and DLBCL. Inhibition of PASK resulted in reduced expression of p-S6 in BHD1-cells. This is the first study demonstrating an mTOR independent p-S6 activity in PCNSL and that PASK may contribute to the phosphorylation of S6. Our findings also suggest a potential role of PASK in the pathomechanism of PCNSL and in DLBCL.

Ribosomal Protein S6: A Potential Therapeutic Target against Cancer?

“…The overexpression of RPS6 confers intrinsic or acquired drug resistance to cancer cells [ 39 , 352 , 353 , 354 , 355 , 356 , 357 , 358 , 359 , 360 ]. RPS6 has been reported to confer drug resistance through nuclear factor erythroid 2-related factor 2 (NRF2) [ 354 ].…”

“…High-level phosphorylation and/or overexpression of RPS6 has been reported in various types of cancers, including acute myeloid leukemia (AML) [ 433 ], breast cancer [ 434 ], cervical cancer [ 435 ], esophageal squamous cell carcinoma (ESCC) [ 436 ], GC [ 437 ], glioblastoma multiforme (GBM) [ 438 ], HNSCC [ 439 ], melanoma [ 440 ], non-Hodgkin’s lymphoma [ 338 ], NSCLC [ 38 ], oral squamous cell carcinoma (OSCC) [ 441 , 442 ], ovarian epithelial cancer (OEC) [ 40 , 443 ], pancreatic cancers [ 13 , 17 , 444 ], renal cell carcinoma (RCC) [ 445 ], sarcoma [ 446 ], and vulva squamous cell carcinoma (VSCC) [ 447 ]. More interestingly, mTOR-independent phosphorylation of RPS6 was frequently identified in primary central nervous system lymphoma (PCNSL) and DLBCL [ 338 , 355 ]. PASK, but not RSK, was found as a potential kinase of RPS6 in these lymphomas [ 355 ].…”

“…More interestingly, mTOR-independent phosphorylation of RPS6 was frequently identified in primary central nervous system lymphoma (PCNSL) and DLBCL [ 338 , 355 ]. PASK, but not RSK, was found as a potential kinase of RPS6 in these lymphomas [ 355 ]. Additionally, RPS6 has been proposed as a predictive biomarker in cancers.…”

“…As mentioned earlier, the overexpression of RPS6 has been implicated in intrinsic or acquired drug resistance of cancer cells (see Section 3.2.4 . Regulation of Drug Resistance) [ 39 , 352 , 353 , 354 , 355 , 356 , 357 , 358 , 359 , 360 ]. More importantly, constitutive phosphorylation of RPS6 has been found to confer drug resistance in breast cancer cells, GC cells, and melanoma cells [ 39 , 359 , 360 ].…”

Decreased Expression of ZNF554 in Gliomas is Associated with the Activation of Tumor Pathways and Shorter Patient Survival

“…Since ZNF554 is a regulator of cell invasion [13], and it has high expression in the brain, our collaborative teams [13,23,24] hypothesized that it may play a role in glioma development. Accordingly, we aimed to examine the expression of ZNF554 both at RNA and protein levels in normal brain and adult diffuse gliomas, as well as the association of ZNF554 expression with patient survival, and to search for genome-wide transcriptomic and proteomic changes in glioblastoma cells transiently overexpressing ZNF554.…”