Pyruvate Kinase M1 Suppresses Development and Progression of Prostate Adenocarcinoma

Abstract

Altered metabolisms helps sustain cancer cell proliferation and survival. Most cancers, including prostate cancers, express the M2 splice isoform of pyruvate kinase (Pkm2), which can support anabolic metabolism to support cell proliferation. However, Pkm2 expression is dispensable for the formation and growth of many cancers in vivo. Expression of pyruvate kinase isoform M1 (Pkm1) is restricted to relatively few tissues and has been reported to promote growth of select tumors, but the role of Pkm1 in cancer has been less studied than Pkm2. To test how differential expression of pyruvate kinase isoforms affects cancer initiation and progression, we generated mice harboring a conditional allele of Pkm1, and crossed these mice or those with a Pkm2 conditional allele with a Pten loss-driven prostate cancer model. Pkm1 loss led to increased Pkm2 expression and accelerated prostate cancer development, while Pkm2 deletion of led to increased Pkm1 expression and suppressed tumor progression. Metabolic profiling revealed altered nucleotide levels in tumors with high Pkm1 expression, and failure of these tumors to progress was associated with DNA replication stress and senescence. Consistent with these data, a small molecule pyruvate kinase activator that mimics a high activity Pkm1-like state suppressed progression of established prostate tumors. Analysis of human specimens showed PKM2 expression is retained in most human prostate cancers. Overall, this study uncovers a role for pyruvate kinase isoforms in prostate cancer initiation and progression, and argues that pharmacological pyruvate kinase activation may be beneficial for treating prostate cancer.

The expression of PKM1 and PKM2 in developing, benign, and cancerous prostatic tissues

“…Given the well-established function of PKM2 in regulating glucose metabolism, elevated PKM2 in high-grade AdPCa aligns well with the increased Warburg effect in these tumors. This notion is further supported by previous studies that have shown PKM2 knockdown reduces lactate production and inhibits cell proliferation in DU145 cells, and Pkm2 knockout suppresses tumor progression in Pten null mice 54,56 . Taken together, these studies indicate that PKM2 promotes Warburg effects and carcinogenesis of AdPCa.…”

“…PKL is mainly expressed in kidney, liver, and intestine, while PKR is expressed predominantly in red blood cells 53 . A recent study found that in prostate, PKM1 is mostly expressed in stromal cells, whereas PKM2 is expressed in both normal epithelia and cancer cells 54 . It has also been shown that the expression level of PKM2 is higher in prostate adenocarcinomas compared to normal human prostatic tissues and even higher in Gleason 8-10 tumors compared to Gleason 6-7 adenocarcinomas 55,56 .…”

Druggable Metabolic Vulnerabilities Are Exposed and Masked during Progression to Castration Resistant Prostate Cancer

“…The lower enzymatic activity of PKM2 compared to PKM1 allows cancer cells to rewire their metabolism and utilize the intermediates of glycolysis for biosynthetic pathways [ 133 ]. Consistently, pharmacological activation of PKM2 by TEPP-46 suppresses tumor progression in PCa models [ 134 ]. Finally, passenger deletion of enolase 1 (ENO1) is associated with homozygous deletion of the 1p36 tumor-suppressor locus, which provides selective vulnerability to a potent prodrug of the competitive ENO2 inhibitor, POMHEX [ 421 , 422 ].…”

“…PKM1 is a constitutively active tetrameric enzyme, while the allosteric binding of 1,6-FBP to PKM2 promotes its tetrameric formation from the less active dimer. An abundance of PKM1 suppresses PCa development by promoting more complete glucose catabolism, thereby limiting glucose entry into the PPP and reducing the production of nucleotides necessary for proliferation [ 134 ]. Alternatively, PKM2 functions as a more typical oncogene, and its overexpression is implicated in multiple cancer types [ 135 , 136 ].…”

Biological role of fructose in the male reproductive system: Potential implications for prostate cancer

“…A similar effect may be occurring in PCa where a small molecule PKM2 activator can suppress progression of established prostate tumors in mice. 92 In the presence of glucose, the addition of fructose enhances glycolysis. For example, Taylor and colleagues showed that lactate production in human colorectal cancer cells is increased by the addition of fructose in either hypoxic or normoxic conditions.…”