Sec61β Controls Sensitivity to Platinum-Containing Chemotherapeutic Agents through Modulation of the Copper-Transporting ATPase ATP7A

Abstract

The Sec61 protein translocon is a multimeric complex that transports proteins across lipid bilayers. We discovered that the Sec61␤ subunit modulates cellular sensitivity to chemotherapeutic agents, particularly the platinum drugs. To investigate the mechanism, expression of Sec61␤ was constitutively knocked down in 2008 ovarian cancer cells. Sec61␤ knockdown (KD) resulted in 8-, 16.8-, and 9-fold resistance to cisplatin (cDDP), carboplatin, and oxaliplatin, respectively. Sec61␤ KD reduced the cellular accumulation of cDDP to 67% of that in parental cells. Baseline copper levels, copper uptake, and copper cytotoxicity were also reduced. Because copper transporters and chaperones regulate platinum drug accumulation and efflux, their expression in 2008 Sec61␤-KD cells was analyzed; ATP7A was found to be 2-to 3-fold overexpressed, whereas there was no change in ATP7B, ATOX1, CTR1, or CTR2 levels. Cells lacking ATP7A did not exhibit increased cDDP resistance upon knockdown of Sec61␤. Sec61␤-KD cells also exhibited altered ATP7A cellular distribution. We conclude that Sec61␤ modulates the cytotoxicity of many chemotherapeutic agents, with the largest effect being on the platinum drugs. This modulation occurs through effects of Sec61␤ on the expression and distribution of ATP7A, which was shown previously to control platinum drug sequestration and cytotoxicity.

A combination of curcumin and oligomeric proanthocyanidins offer superior anti-tumorigenic properties in colorectal cancer

“…2E , top left). Similarly, the mRNA level of Sec61b, a protein involved in modulating sensitivity to platinum-based chemotherapeutic agents such as oxaliplatin and cisplatin 38 , showed a greater increase with the combination of OPCs and curcumin, vis-à-vis, individual agents (Fig. 2E , top right).…”

“…Several genes that were identified and validated in our study to be cooperatively modulated by OPCs and curcumin are also implicated in the development of chemo-resistance. SEC61B is essential for platinum drug accumulation, and its knockdown desensitizes cancer cells to oxaliplatin, carboplatin and cisplatin 38 , while G6PD and PDE3B enhance chemoresistance to oxaliplatin and cisplatin 39 , 54 . OPCs and curcumin together influenced several ABC transporters (Supplemental Fig.…”

Organ-specific regulation of ATP7A abundance is coordinated with systemic copper homeostasis

“…A previous report showing no changes in Atp7a mRNA levels in response to supplemental Cu in rat IECs 21 suggests steady-state ATP7A protein levels are regulated post-transcriptionally. ATP7A is very stable protein, with a reported half-life of over 40 h in a variety of cells 21 , 28 – 30 . To further explore Cu-dependent ATP7A regulation, IEC-6 cells were treated with Cu or BCS in the presence of the translation inhibitor cycloheximide (CHX), and steady-state levels of ATP7A were analyzed by immunoblotting over time.…”

DNA Damage and Transcriptional Changes in the Gills of Mytilus galloprovincialis Exposed to Nanomolar Doses of Combined Metal Salts (Cd, Cu, Hg)

“…At the 200 nM metal dose, we also found significantly over-expressed transcripts denoting SEC 61 and SEC 63. In the endoplasmic reticulum, the Sec 61 multimeric complex allows the protein translocation across lipid bilayers, the backward transport of proteins destined to ubiquitination and proteosomal degradation, and it modulates the intracellular trafficking and cytotoxicity of cisplatin and copper, elements whose divalent ions display similar sulfur-binding properties [65].…”