BCKDK of BCAA Catabolism Cross-talking With the MAPK Pathway Promotes Tumorigenesis of Colorectal Cancer

Abstract

Branched-chain amino acids catabolism plays an important role in human cancers. Colorectal cancer is the third most commonly diagnosed cancer in males and the second in females, and the new global incidence is over 1.2 million cases. The branched-chain α-keto acid dehydrogenase kinase (BCKDK) is a rate-limiting enzyme in branched-chain amino acids catabolism, which plays an important role in many serious human diseases. Here we investigated that abnormal branched-chain amino acids catabolism in colorectal cancer is a result of the disease process, with no role in disease initiation; BCKDK is widely expressed in colorectal cancer patients, and those patients that express higher levels of BCKDK have shorter survival times than those with lower levels; BCKDK promotes cell transformation or colorectal cancer ex vivo or in vivo. Mechanistically, BCKDK promotes colorectal cancer by enhancing the MAPK signaling pathway through direct MEK phosphorylation, rather than by branched-chain amino acids catabolism. And the process above could be inhibited by a BCKDK inhibitor, phenyl butyrate.

Branched-chain amino acids sustain pancreatic cancer growth by regulating lipid metabolism

“…To explore the roles of BCAA metabolism in PDAC proliferation, we next tested the effect of BCKDHA knockdown on PDAC cell proliferation. BCKDHA, the enzyme catalyst for the second step of the BCAA catabolic pathway, which has a central role in the regulation of BCAA catabolism, has been shown to promote tumorigenesis that leads to colorectal cancer 28 . Consistent with this finding, BCKDHA knockdown significantly reduced PDAC cell proliferation (Fig.…”

“…Thus, it is possible that the catabolism of these elevated levels of BCAA may play a critical role in tumor growth. Indeed, genetic disruption of the key enzymes involved in BCAA catabolism inhibits the growth of tumors 17–19,28 . Our data also showed that knockdown of either BCAT2 or BCKDHA significantly inhibited PDAC cell proliferation but not HPDE cell proliferation (Figs.…”

“…BCKDHA has been shown to promote the tumorigenesis that leads to colorectal cancer 28 . It is a key enzyme in the BCAA catabolic pathway that generates acetyl-CoA from BCAAs fuel the TCA cycle 25 .…”

Multifaceted role of branched-chain amino acid metabolism in cancer

“…BCKDK is upregulated in colorectal tumors and its expression promotes colorectal tumor growth and metastasis in mice [ 58 , 59 ]. Xue P et al .…”

“…Xue P et al . showed that BCKDK directly phosphorylates MEK1 at serine 221 in colorectal cancer cells in vitro leading to activation of MAPK signaling [ 58 ]. MAPK has a broad function in cancer cell proliferation and thus the BCKDK-MEK1 axis may contribute to colorectal cancer development.…”