Role of SPTSSB-Regulated de Novo Sphingolipid Synthesis in Prostate Cancer Depends on Androgen Receptor Signaling

Abstract

Anti-androgens are a common therapy in prostate cancer (PCa) targeting androgen receptor (AR) signaling. However, these therapies fail due to selection of highly aggressive AR-negative cancer cells that have no therapeutic options available. We demonstrate that elevating endogenous ceramide levels with administration of exogenous ceramide nanoliposomes (CNLs) was efficacious in AR-negative cell lines with limited efficacy in AR-positive cells. This effect is mediated through reduced de novo sphingolipid synthesis in AR-positive cells. We show that anti-androgens elevate de novo generation of sphingolipids via SPTSSB, a rate-limiting mediator of sphingolipid generation. Moreover, pharmacological inhibition of AR increases the efficacy of CNL in AR-positive cells through de novo synthesis, while SPTSSB knockdown limited CNL's efficacy in AR-negative cells. Alluding to clinical relevance, SPTSSB is upregulated in patients with advanced PCa after anti-androgens treatment. These findings emphasize the relevance of AR regulation upon sphingolipid metabolism and the potential of CNL as a PCa therapeutic.

Chaihu-Shugan-San ameliorates tumor growth in prostate cancer promoted by depression via modulating sphingolipid and glycerinphospholipid metabolism

“…Phosphate esters such as PC and PE are the main components of cell membranes, and changes in their chain length can directly cause changes in membrane fluidity, which in turn affects membrane permeability, material transport, and the localization of membrane proteins ( Chen et al, 2018 ; Galbraith et al, 2018 ; Di Mitri et al, 2019 ; Watt et al, 2019 ; Blomme et al, 2020 ; Centenera et al, 2021 ). Sphingolipids are also involved in cancer cell biology at multiple levels ( Furuya et al, 2011 ; Costa-Pinheiro et al, 2020 ; Vykoukal et al, 2020 ; Lin et al, 2021a ; Lin et al, 2021b ).…”

Nanoliposome C6‐Ceramide in combination with anti‐CTLA4 antibody improves anti‐tumor immunity in hepatocellular cancer

“…Phase I clinical trial of the patented LipC6 has been recently completed (NCT#02834611). 40 Our recent studies led to the new findings that LipC6 has the capacity to break HCC-induced immune tolerance. 17 Of particular importance, we have now demonstrated that LipC6 treatment significantly improves αCTLA-4 Ab's therapeutic suppression on HCC.…”

Ceramide Metabolism Enzymes—Therapeutic Targets against Cancer

“…ssSPT subunits have been described as important regulators of SPT activity. Recently, it has been observed that in patients with prostate cancer treated with anti-androgens treatment, an increase in the expression of SPTSSB was detected [ 70 ]. Moreover, administration of exogenous Cer nanoliposomes was determined as an efficient treatment in cancer cells [ 70 ].…”

“…Recently, it has been observed that in patients with prostate cancer treated with anti-androgens treatment, an increase in the expression of SPTSSB was detected [ 70 ]. Moreover, administration of exogenous Cer nanoliposomes was determined as an efficient treatment in cancer cells [ 70 ]. In addition to ssSPT subunits, the Tsc3 subunit was found to be a potent regulatory protein of SPT, increasing its activity by up to 50-fold [ 71 , 72 ].…”