Rapamycin synergizes cisplatin sensitivity in basal-like breast cancer cells through up-regulation of p73

Abstract

Recent gene expression profiling studies have identified five breast cancer subtypes, of which the basal-like subtype is the most aggressive. Basal-like breast cancer poses serious clinical challenges as there are currently no targeted therapies available to treat it. Although there is increasing evidence that these tumors possess specific sensitivity to cisplatin, its success is often compromised due to its dose-limiting nephrotoxicity and the development of drug resistance. To overcome this limitation, our goal was to maximize the benefits associated with cisplatin therapy through drug combination strategies. Using a validated kinase inhibitor library, we showed that inhibition of the mTOR, TGFβRI, NFκB, PI3K/AKT, and MAPK pathways sensitized basal-like MDA-MB-468 cells to cisplatin treatment. Further analysis demonstrated that the combination of the mTOR inhibitor rapamycin and cisplatin generated significant drug synergism in basal-like MDA-MB-468, MDA-MB-231, and HCC1937 cells but not in luminal-like T47D or MCF-7 cells. We further showed that the synergistic effect of rapamycin plus cisplatin on basal-like breast cancer cells was mediated through the induction of p73. Depletion of endogenous p73 in basal-like cells abolished these synergistic effects. In conclusion, combination therapy with mTOR inhibitors and cisplatin may be a useful therapeutic strategy in the treatment of basal-like breast cancers.

A balancing act: orchestrating amino-truncated and full-length p73 variants as decisive factors in cancer progression

“…For example, the mTOR inhibitor rapamycin activates TAp73-mediated gene expression and sensitizes aggressive cancer cells to CDDP treatment. 58,163 Pharmacological stimulation of AMP-activated protein kinase leads to accumulation of TAp73 in the nucleus via direct phosphorylation and causes apoptosis, however, only in the presence of p53. 164 Smallmolecule inhibitors of phosphatidylinositol 3′-kinase, AKT or prodigiosin disrupt the inhibitory effect of mutant p53 on TAp73.…”

CYP2S1 and CYP2W1 Mediate 2-(3,4-Dimethoxyphenyl)-5-Fluorobenzothiazole (GW-610, NSC 721648) Sensitivity in Breast and Colorectal Cancer Cells

“…High-titer lentiviral stocks were generated by cotransfection with packaging plasmids psPAX2 (Addgene plasmid 12260) and envelope plasmids pMD2.G (Addgene plasmid 12259) into HEK-293T cells as reported previously (19)(20)(21)(22)(23). The shRNA target sequences for CYP1A1, CYP2S1, and CYP2W1 are shown in Supplementary Table S2.…”

Eradication of metastatic melanoma through cooperative expression of RNA-based HDAC1 inhibitor and p73 by oncolytic adenovirus

“…Earlier studies showed that both, p73 and chemical inhibitors of HDAC1, like suberoylanilide hydroxamic acid (SAHA), are capable to induce autophagy in addition to apoptosis [53, 54]. The mammalian target of rapamycin (mTOR), another protein with key functions in cell growth and proliferation, for example, is able to regulate p73, and treatment with rapamycin sensitizes highly aggressive breast cancer cells to cisplatin through upregulation of TAp73 [55-57]. Our results revealed that the levels of autophagy induction measured as autophagic flux represented by the ratio of autophagosomal microtubule-associated protein 1A/1B-light chain 3 (LC3-II) to cytosolic (LC3-I) protein, differed considerably between the viruses used in this study.…”