Tumor Pro-oxidant Enviroment Stabilizes Onco-protein c-Myc via Sustained Phosphorylation at Serine 62 that Promotes its Oncogenic Activity

ATPase which helps to maintain a cytosolic pH optimal for

degradation by the 26S proteasome. Hitherto driven c-Myc

glycolysis.

stability is further complemented with a moderate increase

Work aimed at establishing which of these

enzymes may be inhibited by PAO is underway. In addition,

in its activity and gain of chemoresistance in osteosarcoma

preliminary results are consistent with the possibility that

cells. This paradigm shift in our understanding of c-Myc

hydrogen peroxide may inhibit cellular proliferation by a

stability as a function of tumor redox microenvironment

pathway similar to PAO, a result which has implications for

could give us valuable cues in providing a pathway for

targeting highly proliferating cancer cells by redox-active

therapeutic

therapeutics.

regulation of c-Myc in human cancer.

intervention

targeting

post-translational

Reference: Low, I et al. Sustained Ser70 phosphorylation of Bcl-2 by selective tyrosine nitration of protein phosphatase

DOI: 10.1016/j.freeradbiomed.2017.10.145

2A-B56δ stabilizes its anti-apoptotic activity.

Blood,

124(4):2223-34, 2014 DOI: 10.1016/j.freeradbiomed.2017.10.146

133 Tumor Pro-oxidant Enviroment Stabilizes Onco-protein c-Myc via Sustained

134

Phosphorylation at Serine 62 that Promotes its Oncogenic Activity

Structural Variations in Selenium Drugs

Deepika Raman1 and Shazib Pervaiz1,2,3

Determine Selective Toxicity towards Triple Negative Breast Cancer

1

National University of Singapore, Singapore

2

National University Cancer Institute, Singapore

3

NUS

Graduate

School

for

Integrative

Sciences

and

Engineering, Singapore c-Myc is arguably one of the most notorious oncoproteins known. c-Myc activity and oncogenic potential, are in turn, intricately regulated by its stabilizing phosphorylation at the Serine 62 (S62) residue. Phosphorylation at the S62 site is mediated cascade,

by

RAS

while

activated

its

RAF/MEK/ERK

dephosphorylation

is

signaling

under

the

governance of the protein phosphatase 2A (PP2A). Our recent work highlighted the critical involvement of cellular redox status, in particular superoxide anion, in inhibiting PP2A-mediated dephosphorylation of Bcl-2 at serine 70, thus stabilizing its anti-apoptotic activity . Here we report 1

that the stabilization and activity of the onco-protein c-myc is

significantly

amplified

microenvironment,

which

by

the

'pro-oxidant'

profoundly

impacted

tumor PP2A

phosphatase activity via nitrative inhibition of the B56α regulatory subunit. The B56α regulatory arm is responsible for delivering PP2A substrate phosphoprotein-c-Myc to the catalytic C subunit within the AC core dimer. Tyrosine nitration of the B56α isoform renders it incapable of binding the

core

dimer

causing

c-Myc

to

remain

hyperphosphorylated at the serine 62 site. Sustained serine 62 phosphorylated c-Myc inhibits its ubiquitination and

98

Jackmil Puthoor Jogy1 and Gregory Giles1 1

University of Otago, New Zealand

Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer affecting approximately 20% of women. TNBC cells lack three key receptors: progesterone, oestrogen and Her2, and as a result, TNBC cannot be treated using existing targeted therapies; therefore patients have an extremely poor prognosis. Recently selenium based drugs have been proposed as therapeutics to treat a range of disorders, and here we investigated the potential of these drugs to target TNBC. Representative selenium compounds diphenyl selenide (DPS) and diphenyl diselenide (DPDS) were characterised by their cytotoxicity against the TNBC cell lines: MDA-MB-231, MDA-MB-468 and HS-578T and, to probe selectivity, against the non-TNBC line SK-BR-3, which expresses Her2. DPS showed no anti-cancer action against any breast cancer cells, however, its structural analogue DPDS showed pronounced cytotoxicity in the range 5-20 μM against all TNBC cell lines studied. Interestingly neither drug displayed cytotoxicity towards a non-TNBC cell line, indicating that DPDS may be capable of selectively destroying TNBC cells without damaging the surrounding healthy cells in the cancerous tissue.

SfRBM 2017