Genes in the Cholesterol Biosynthetic Pathway Protect Cancer Cells from Chemotherapy

Two genes that encode for proteins involved in cholesterol metabolism have been linked to the ability of cancer cells to develop resistance to chemotherapeutic drugs.

Investigators at the Fox Chase Cancer Center (Philadelphia, PA, USA) worked with both human cancer cells growing in culture and with a mouse xenograft-model system. They focused their study on the oncogenic signaling protein epidermal growth factor receptor (EGFR) and its inhibitors.

They reported in the January 2013 issue of the journal Cancer Discovery that inactivation of two genes whose protein products were localized to the endoplasmic reticulum and involved in cholesterol biosynthesis could sensitize cancer cells to the effects of anti-EGFR drugs. The role of the two genes, SC4MOL (sterol C4-methyl oxidase-like) and NSDHL (NADP-dependent steroid dehydrogenase-like), had been predicted by bioinformatics modeling of interactions of the genes in the sterol biosynthetic pathway and then extensively validated in laboratory studies.

Results of the in vitro studies confirmed the importance of SC4MOL and NSDHL in controlling the signaling, vesicular trafficking, and degradation of EGFR and its dimerization partners, ERBB2 and ERBB3. Blocking the metabolic pathway upstream of SC4MOL with ketoconazole or CYP51A1 siRNA rescued cancer cell viability and halted EGFR degradation. Inactivation of SC4MOL markedly sensitized A431 xenografts to cetuximab, a therapeutic anti-EGFR antibody.

"Most tumors are only moderately sensitive to inhibitors of EGFR, but when these tumors lack an essential gene in the cholesterol pathway, they become exquisitely sensitive to the anti-EGFR drugs," said senior author Dr. Igor Astsaturov, professor of medical oncology at the Fox Chase Cancer Center. "The cancers literally melt away in mice. Ideally, this research will eventually enable scientists to find drugs that disrupt this pathway and boost the impact of current therapies. That is the long-term plan."

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