Increased Serine and One-Carbon Pathway Metabolism by PKCλ/ι Deficiency Promotes Neuroendocrine Prostate Cancer

Abstract

Graphical AbstractHighlights d Loss of PKCl/i promotes basal and NEPC features in vivo d PKCl/i represses mTORC1 activation through LAMTOR2 phosphorylation d Loss of PKCl/i increases the SGOCP through mTORC1/ATF4 to fuel DNA methylation d The mTORC1/ATF4/PHGDH axis is a synthetic vulnerability of NEPC SUMMARY Increasingly effective therapies targeting the androgen receptor have paradoxically promoted the incidence of neuroendocrine prostate cancer (NEPC), the most lethal subtype of castration-resistant prostate cancer (PCa), for which there is no effective therapy. Here we report that protein kinase C (PKC)l/i is downregulated in de novo and during therapy-induced NEPC, which results in the upregulation of serine biosynthesis through an mTORC1/ATF4-driven pathway. This metabolic reprogramming supports cell proliferation and increases intracellular S-adenosyl methionine (SAM) levels to feed epigenetic changes that favor the development of NEPC characteristics. Altogether, we have uncovered a metabolic vulnerability triggered by PKCl/i deficiency in NEPC, which offers potentially actionable targets to prevent therapy resistance in PCa.

The complexity of the serine glycine one-carbon pathway in cancer

“…In PCa, increased SAM production via an mTORC1-mediated up-regulation of the activating transcription factor 4 (ATF4)/ SGOCP axis by PKCλ/ι deficiency was found to contribute to increased cell lineage plasticity and to the acquisition of resistance to targeted therapy in human cancer cell lines and in vivo mouse models (Reina-Campos et al, 2019). In this context, the inhibition of PHGDH or of the DNA methyltransferase activity was able to reestablish normal SAM pools and to rescue cell differentiation and proliferation in vitro and in vivo (Reina-Campos et al, 2019). PKCλ/ι-deficient cells also showed increased incorporation of methionine-derived carbons into 5methyl-cytosine, which depended on extracellular serine (Reina-Campos et al, 2019).…”

“…In this context, the inhibition of PHGDH or of the DNA methyltransferase activity was able to reestablish normal SAM pools and to rescue cell differentiation and proliferation in vitro and in vivo (Reina-Campos et al, 2019). PKCλ/ι-deficient cells also showed increased incorporation of methionine-derived carbons into 5methyl-cytosine, which depended on extracellular serine (Reina-Campos et al, 2019). This suggests that while the de novo synthesis of serine was increased by PKCλ/ι deficiency, it was likely not enough to prevent serine starvation from affecting SAM pools (Reina-Campos et al, 2019; Fig.…”

“…An additional line of research is focused on finding new actionable metabolic drivers of tumorigenesis. PHGDH is being actively pursued as a key metabolic vulnerability in tumors, as previously discussed (Mullarky et al, 2016;Pacold et al, 2016;Reina-Campos et al, 2019;Wang et al, 2017). For example, PHGDH inhibition is effective in the context of HIF2α-deficient clear cell renal cell carcinoma (Yoshino et al, 2017).…”

“…Other enzymes of the SGOCP play a key role in tumorigenesis. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is consistently up-regulated in many cancer types, and its expression significantly correlates with poor clinical outcome in breast cancer, pancreatic carcinomas, renal cell carcinoma, and leukemia and in a particularly aggressive metabolic subtype of hepatocellular carcinoma (HCC; Bidkhori et al, 2018;Lehtinen et al, 2013;Lin et al, 2018;Liu et al, 2014;Nilsson et al, 2014;Noguchi et al, 2018;Reina-Campos et al, 2019;Tedeschi et al, 2015). MTHFD2 is a dual-action enzyme (dehydrogenase and cyclohydrolase) that catalyzes the reversible conversion of 5,10methylene-THF into 10-formyl-THF in the mitochondria, while MTHFD1, its cytosolic counterpart, catalyzes an extra reaction (synthetase) to convert 10-formyl-THF into THF and formate ( Fig.…”

“…Indeed, basal and stem cell genetic programs are activated during the development of acquired resistance through mechanisms of cellular plasticity (Davies et al, 2018;Smith et al, 2015). Drug resistance also occurs through increased SGOCP activity in PCa, melanoma, pancreatic carcinomas, and non-small cell lung carcinoma (NSCLC; Reina-Campos et al, 2019;Ross et al, 2017). The less proliferative nature of TICs might underlie their different utilization of key aspects of the SGOCP, likely by shifting the pathway output from nucleotide generation to that of a reductive environment and the synthesis of SAM.…”