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Abstract
Elucidating signaling pathways that regulate cellular metabolism is essential for a better understanding of normal development and tumorigenesis. Recent studies have shown that mitochondrial pyruvate carrier 1 (MPC1), a crucial player in pyruvate metabolism, is downregulated in colon adenocarcinomas. Utilizing zebrafish to examine the genetic relationship between MPC1 and Adenomatous polyposis coli (APC), a key tumor suppressor in colorectal cancer, we found that apc controls the levels of mpc1 and that knock down of mpc1 recapitulates phenotypes of impaired apc function including failed intestinal differentiation. Exogenous human MPC1 RNA rescued failed intestinal differentiation in zebrafish models of apc deficiency. Our data demonstrate a novel role for apc in pyruvate metabolism and that pyruvate metabolism dictates intestinal cell fate and differentiation decisions downstream of apc.
Highlights
Mutations in the adenomatous polyposis coli (APC) gene are responsible for Familial Adenomatous Polyposis (FAP), a genetic predisposition to colorectal cancer, and are found in the majority of sporadic colonic tumors (Fearnhead et al, 2001)
We looked at other genes involved in pyruvate transport and metabolism and interestingly, mitochondrial pyruvate carrier 1 (MPC1), MPC2, PDHA1 and pyruvate carboxylase (PC) showed consistent downregulation in a specific subset of colon adenocarcinomas known as colon mucinous adenocarcinomas (AC) (n = 22) (Figure 6—figure supplement 1A)
We demonstrate a direct relationship between loss of a key tumor suppressor gene, APC, and dysregulation of MPC1
Summary
Mutations in the adenomatous polyposis coli (APC) gene are responsible for Familial Adenomatous Polyposis (FAP), a genetic predisposition to colorectal cancer, and are found in the majority of sporadic colonic tumors (Fearnhead et al, 2001). Experiments with zebrafish – a model animal that is commonly used in the field of cancer biology – showed that APC acts via mpc to regulate how the cell uses energy This regulation goes awry in colon cells that have abnormal APC activity; restoring the cell’s metabolism back to normal was enough to induce cells in the intestine to develop properly. Consistent with a causative role in tumorigenesis, re-expression of MPC1 repressed the Warburg effect in colon cancer cell lines (Schell et al, 2014) It is not clear how MPC1 is regulated or how its activities relate to the known genetic events that contribute to colon cancer development. Our findings strongly suggest that changes in metabolic profile can drive cell fate and differentiation decisions
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