EGFR-SGLT1 interaction does not respond to EGFR modulators, but inhibition of SGLT1 sensitizes prostate cancer cells to EGFR tyrosine kinase inhibitors

Abstract

These data suggest that EGFR in cancer cells can exist as either a tyrosine kinase modulator responsive status or an irresponsive status. SGLT1 is a protein involved in EGFR's functions that are irresponsive to EGFR tyrosine kinase inhibitors and, therefore, the EGFR-SGLT1 interaction might be a novel target for prostate cancer therapy.

A Review on the Relationship between SGLT2 Inhibitors and Cancer

“…In humans, SGLT1 is overexpressed in many cancers [19, 40]. Inhibition of SGLT1 sensitizes prostate cancer cells to treatment with EGFR (epidermal growth factor receptor) tyrosine kinase inhibitor [40].…”

“…Inhibition of SGLT1 sensitizes prostate cancer cells to treatment with EGFR (epidermal growth factor receptor) tyrosine kinase inhibitor [40]. High SGLT1 level combined with high MAP17 (membrane-associated protein 17) is a marker for good prognosis in patients with cervical cancer after chemotherapy and radiotherapy [41].…”

Involvement of de novo synthesized palmitate and mitochondrial EGFR in EGF induced mitochondrial fusion of cancer cells

“…Previously, we have reported that EGFR interacts and stabilizes the sodium/glucose co-transporter 1 (SGLT1) independent of EGFR's tyrosine kinase activity. 52,53 It is intriguing that the proteins found to interact with EGFR independent of EGFR's tyrosine kinase activity all own prosurvival functions, SGLT1 for glucose uptake, PHB2 for mitochondrial integrity, FASN for de novo fatty acids synthesis. Considering the facts that only about 10-20% of patients of solid cancers respond to treatment of EGFR tyrosine kinase inhibitors [54][55][56] and EGFR is overexpressed in the majority of cancers of epithelial origin, 57,58 i.e., there is a majority of patients with EGFR positive cancers do not respond well to the inhibition of EGFR's tyrosine kinase, we argue that a possibility exists, which is that EGFR can promote cancer progression via mechanisms that are independent of its tyrosine kinase activity.…”

Role of ion channels in ionizing radiation-induced cell death

“…SGLT has been shown to be in complex with the EGFR [50,53] and radiogenic SGLT activation depends on EGFR tyrosine kinase activity [43]. Importantly, radiogenic increase in glucose fuelling seems to be required for cell survival since the SGLT inhibitor phlorizin radiosensitizes A549 lung adenocarcinoma and FaDu head and neck squamous carcinoma cells [43].…”

“…SGLTs allow efficient glucose uptake even from a glucose-depleted microenvironment which is typical for malperfused solid tumors [44]. It is therefore not surprising that several tumor entities such as colorectal, pancreatic, lung, head and neck, prostate, kidney, cervical, breast, bladder and prostate cancer as well as chondrosarcomas and leukemia upregulate SGLTs [45][46][47][48][49][50][51][52][53].…”