<p>Methylcrotonoyl-CoA Carboxylase 2 Promotes Proliferation, Migration and Invasion and Inhibits Apoptosis of Prostate Cancer Cells Through Regulating GLUD1-P38 MAPK Signaling Pathway</p>

Abstract

Prostate cancer (PCa) is the most common cancer in American men, and the mechanisms of development and progression are still not completely clear. Methylcrotonoyl-CoA carboxylase 2 (MCCC2) was previously identified overexpressed in PCa with lymph node metastasis, but its specific role and mechanisms need further investigation. This study aimed to investigate the role of MCCC2 in PCa cells and its underlying mechanisms. Materials and Methods: Quantitative RT-PCR and Western blotting were used to detect MCCC2 mRNA and protein expression in normal prostate epithelium and cancerous cells. Upon manipulation of MCCC2 expression, cell proliferation was measured by CCK-8 assays and migration and invasion were determined by transwell assays. Changes of apoptosis, cell cycle and mitochondrial membrane potential were evaluated by flow cytometry. MCCC2-mediated signaling pathways were screened by bioinformatics and verified by RT-PCR and Western blotting. Finally, immunohistochemistry was performed to detect the expression of MCCC2 and glutamate dehydrogenase 1 (GLUD1) in PCa tissues to analyze their correlation. Results: We demonstrated that MCCC2 promoted cell proliferation, migration and invasion but inhibited apoptosis in PCa cells. In addition, MCCC2 in 22Rv1 cells induced mitochondrial damage. In PCa tissues, MCCC2 overexpression associated with lymph node metastasis (P=0.001) and high Gleason scores (P<0.001). MCCC2 positively correlated with GLUD1 expression in PCa tissues (r=0.435, P<0.001). Ectopic overexpression of MCCC2 up-regulated GLUD1 and p38 MAPK expression, whereas inhibition of MCCC2 decreased GLUD1 and p38 MAPK expression. Conclusion: MCCC2 exerts oncogenic function in PCa through regulating GLUD1-p38 MAPK signaling pathway, and it may be a potential treatment target.

Expression of 3-Methylcrotonyl-CoA Carboxylase in Brain Tumors and Capability to Catabolize Leucine by Human Neural Cancer Cells

“…Even though the number of analyzed tumor samples is limited, these results suggest that leucine can be a metabolic substrate for brain tumor cells. The expression of the MCC has also been confirmed previously in various breast [30], prostate [29,63], colorectal [31], and hepatocellular [32] tumors. Furthermore, several studies revealed novel signaling and regulatory functions intervened by the smaller subunit of MCC, MCCC2, in cancer cells [29,32].…”

“…The expression of the MCC has also been confirmed previously in various breast [30], prostate [29,63], colorectal [31], and hepatocellular [32] tumors. Furthermore, several studies revealed novel signaling and regulatory functions intervened by the smaller subunit of MCC, MCCC2, in cancer cells [29,32]. In this respect, MCCC2 can affect the intracellular signaling cascade facilitated by promoting the activation of ERK in the cytosol of human hepatocarcinoma cells [32] or regulating the GLUD1-P38 MAPK signaling pathway in [29] prostate cancer cells.…”

“…Furthermore, several studies revealed novel signaling and regulatory functions intervened by the smaller subunit of MCC, MCCC2, in cancer cells [29,32]. In this respect, MCCC2 can affect the intracellular signaling cascade facilitated by promoting the activation of ERK in the cytosol of human hepatocarcinoma cells [32] or regulating the GLUD1-P38 MAPK signaling pathway in [29] prostate cancer cells. MCCC2 also exerts its regulatory function on cell proliferation and migration capabilities [29][30][31][32].…”

“…The mutations in MCC subunit genes lead to MCC deficiency (MIM# 210200 and MIM# 210210), an autosomal recessive disorder with a very variable phenotype [28]. The increased expression of MCC promotes proliferation of prostate [29], breast [30], and colorectal cancer cells [31] and is critical for the oncogenesis of hepatocellular carcinoma [32].…”

MCCC2 promotes HCC development by supporting leucine oncogenic function

“…For example, the high expression of MCCC2 predicts a poor prognosis and can promote cell proliferation in colorectal and breast cancer [ 19 , 22 ]. The oncogenic role of MCCC2 is partially involved in the GLUD1-P38 MAPK signaling pathway [ 23 ]. However, it is currently unclear whether MCCC2 also plays an important role in the progression of HCC and the effect of MCCC2 on leucine metabolism has yet not been deciphered.…”